Novel processes for the preparation of piperazinyl and diazapanyl benzamide derivatives

ABSTRACT

The present invention is directed to novel processes for the preparation of substituted piperazinyl and diazepanyl benzamides, useful for the treatment of disorders and conditions mediated by the histamine receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/731,941 filed on Oct. 31, 2005, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to processes for the preparation ofpiperazinyl and diazepanyl benzamide derivatives, useful for thetreatment of disorders and conditions mediated by the histaminereceptor.

BACKGROUND OF THE INVENTION

US Patent Application Publication 2004-0110746 A1, published Apr. 21,2005 (also published as PCT Publication WO 04/037801, May 6, 2004),which is hereby incorporated by reference, discloses novel piperazinyland diazepanyl benzamide derivatives useful for the treatment ofhistamine receptor mediated disorders. More specifically, the compoundsare useful for the treatment of disorders and conditions mediated by theH₃ receptor. More particularly, the compounds are useful for treating orpreventing neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis in a subject in need thereof. For example, methodsfor preventing, inhibiting the progression of, or treating upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitis.

US Patent Application Publication 2004-0110746 A1, published Apr. 21,2005 (also published as PCT Publication WO 04/037801, May 6, 2004)discloses a process for the preparation of the piperazinyl anddiazepanyl benzamides. There remains a need for processes for thepreparation of piperazinyl and diazepanyl benzamide derivatives that aresuitable for large scale/commercial applications.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation ofcompounds of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof;

wherein

R¹ is selected from the group consisting of C₁₋₁₀alkyl, C₃₋₈ alkenyl,C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl, (C₃₋₈cycloalkyl)C₃₋₈alkenyland (C₁₋₈alkylcarbonyl)C₁₋₈alkyl;

n is an integer from 1 to 2;

R² and R³ are each independently selected from hydrogen, fluoro, chloro,bromo, nitro, trifluoromethyl, methyl, or C₁₋₃alkoxy;

m is an integer from 1 to 7; (preferably, m is an integer from 1 to 4,more preferably, m is 1);

Q is NR⁸R⁹;

wherein R⁸ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl(preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene;

and R⁹ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl,6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene;

alternatively, Q is a saturated 3-12 membered N-linked heterocyclyl,wherein, in addition to the N-linking nitrogen, the 3-12 memberedheterocyclyl may optionally contain between 1 and 3 additionalheteroatoms independently selected from O, S, and NH;

wherein Q (when Q is a saturated 3-12 membered N-linked heterocyclyl) isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydroxy, halo, carboxamide, C₁₋₆alkyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃alkylene, C₁₋₆alkoxy, (C₃₋₆cycloalkyl)-O—,phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—;

where each of the above heterocyclyl, phenyl, and alkyl groups may befurther optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of trifluoromethyl,methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;

provided that the 5- and 6-positions on the phenyl ring areunsubstituted (i.e., the R², R³ and —(CH₂)_(m)-Q are bound to the 2-, 3-and 4- positions on the phenyl ring);

provided further that when R¹ is methyl, then —(CH₂)_(m)-Q is notpiperidin-1-ylmethyl;

and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from the group consisting of trifluoromethyl, methoxy, halo,amino, nitro, hydroxy and C₁₋₃ alkyl;

comprising

reacting a compound of formula (X); in a first organic solvent; to yieldthe corresponding compound of formula (XI), wherein L is a leavinggroup; and wherein the compound of formula (XI) is not isolated;

reacting the compound of formula (XI) with a compound of formula (XII);in the presence of an organic or inorganic base; in a second organicsolvent; to yield the corresponding compound of formula (XIII); whereinthe compound of formula (XIII) is not isolated;

and reacting the compound of formula (XIII) with a compound of formula(XIV); in the presence of a reducing agent; in a third organic solvent;to yield the corresponding compound of formula (I).

The present invention is further directed to improvements to analternate process for the preparation of compounds of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof;

wherein

R¹ is selected from the group consisting of C₁₋₁₀oalkyl, C₃₋₈ alkenyl,C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl, (C₃₋₈ cycloalkyl)C₃₋₈alkenyl and (C₁₋₈alkylcarbonyl)C₁₋₈alkyl;

n is an integer from 1 to 2;

R² and R³ are each independently selected from hydrogen, fluoro, chloro,bromo, nitro, trifluoromethyl, methyl, or C₁₋₃alkoxy;

m is an integer from 1 to 7; (preferably, m is an integer from 1 to 4,more preferably, m is 1);

Q is NR⁸R⁹;

wherein R⁸ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl(preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene;

and R⁹ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl,6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene;

alternatively, Q is a saturated 3-12 membered N-linked heterocyclyl,wherein, in addition to the N-linking nitrogen, the 3-12 memberedheterocyclyl may optionally contain between 1 and 3 additionalheteroatoms independently selected from O, S, and NH;

wherein Q (when Q is a saturated 3-12 membered N-linked heterocyclyl) isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydroxy, halo, carboxamide, C₁₋₆alkyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃alkylene, C₁₋₆alkoxy, (C₃₋₆cycloalkyl)-O—,phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—;

where each of the above heterocyclyl, phenyl, and alkyl groups may befurther optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of trifluoromethyl,methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;

provided that the 5- and 6- positions on the phenyl ring areunsubstituted (i.e., the R², R³ and —(CH₂)_(m)-Q are bound to the 2-, 3-and 4- positions on the phenyl ring);

provided further that when R¹ is methyl, then —(CH₂)_(m)-Q is notpiperidin-1-ylmethyl;

and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from the group consisting of trifluoromethyl, methoxy, halo,amino, nitro, hydroxy and C₁₋₃ alkyl;

comprising

reacting a compound of formula (XIII) with a source of bisulfite; in apolar organic solvent; to yield the corresponding compound of formula(XVII);

and reacting the compound of formula (XVII) with a compound of formula(XIV); in the presence of a reducing agent; in the presence of anorganic or inorganic base; in an organic solvent; to yield thecorresponding compound of formula (I).

The present invention is further directed to improvements to analternate process for the preparation of compounds of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof;

wherein

R¹ is selected from the group consisting of C₁₋₁₀alkyl, C₃₋₈ alkenyl,C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl, (C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈alkylcarbonyl)C₁₋₈alkyl;

n is an integer from 1 to 2;

R² and R³ are each independently selected from hydrogen, fluoro, chloro,bromo, nitro, trifluoromethyl, methyl, or C₁₋₃alkoxy;

m is an integer from 1 to 7; (preferably, m is an integer from 1 to 4,more preferably, m is 1);

Q is NR⁸R⁹;

wherein R⁸ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl,phenyl, (6-9-membered heterocyclyl)C₁₋₆alkylene and(phenyl)C₁₋₆alkylene;

and R⁹ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl,6-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,(6-9-membered heterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene;

alternatively, Q is a saturated 3-12 membered N-linked heterocyclyl,wherein, in addition to the N-linking nitrogen, the 3-12 memberedheterocyclyl may optionally contain between 1 and 3 additionalheteroatoms independently selected from O, S, and NH;

wherein Q (when Q is a saturated 3-12 membered N-linked heterocyclyl) isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydroxy, halo, carboxamide, C₁₋₆alkyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃alkylene, C₁₋₆alkoxy, (C₃₋₆cycloalkyl)-O—,phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—;

where each of the above heterocyclyl, phenyl, and alkyl groups may befurther optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of trifluoromethyl,methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;

provided that the 5- and 6- positions on the phenyl ring areunsubstituted (i.e., the R², R³ and —(CH₂)_(m)-Q are bound to the 2-, 3-and 4- positions on the phenyl ring);

provided further that when R¹ is methyl, then —(CH₂)_(m)-Q is notpiperidin-1-ylmethyl;

and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from the group consisting of trifluoromethyl, methoxy, halo,amino, nitro, hydroxy and C₁₋₃ alkyl;

comprising

reacting a compound of formula (XIII) with a source of bisulfite; in apolar organic solvent; to yield the corresponding compound of formula(XVII);

reacting the compound of formula (XVI I) with an organic or inorganicbase; in an organic solvent; to yield the corresponding compound offormula (XIII);

and reacting the compound of formula (XIII) with a compound of formula(XIV); in the presence of a reducing agent; in an organic solvent; toyield the corresponding compound of formula (I).

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (Ia)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof.

In another embodiment, the present invention is directed to processesfor the preparation of a compound of formula (Is)

also known as(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,or a pharmaceutically acceptable salt, ester, tautomer, solvate or amidethereof.

The present invention is further directed to novel crystalline salts ofthe compound of formula (I). In an embodiment, the present invention isdirected to a maleate, succinate, fumarate, hydrochloride orhydrobromode salt of the compound of formula (I).

In an embodiment, the present invention is directed to novel crystallinesalts of the compound of formula (Is). In an embodiment, the presentinvention is directed to a maleate, succinate, fumarate, hydrochlorideor hydrobromide salt of the compound of formula (Is). In anotherembodiment, the present invention is directed to a crystalline succinatesalt of the compound of formula (Is). In another embodiment, the presentinvention is directed to a crystalline mono-succinate salt of thecompound of formula (Is).

The present invention is further directed to a product preparedaccording to any of the processed described herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a succinate salt of thecompound of formula (Is) as described herein. An illustration of theinvention is a pharmaceutical composition made by mixing a succinatesalt of the compound of formula (Is) as described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing asuccinate salt of the compound of formula (Is) as described herein and apharmaceutically acceptable carrier.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a product prepared accordingto any of the processes described herein. An illustration of theinvention is a pharmaceutical composition made by mixing a productprepared according to any of the processes described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing aproduct prepared according to any of the processes described herein anda pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby histamine, preferably, the H₃ histamine receptor, (selected from thegroup consisting of neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis) comprising administering to a subject in needthereof, a therapeutically effective amount of a succinate salt of thecompound of formula (Is) as described herein or pharmaceuticalcomposition comprising a succinate salt of the compound of formula (Is)as described above.

Exemplifying the invention are methods of treating a disorder mediatedby histamine, preferably, the H₃ histamine receptor, (selected from thegroup consisting of neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis) comprising administering to a subject in needthereof, a therapeutically effective amount of a product preparedaccording to any of the processes described herein or a pharmaceuticalcomposition as described above.

Another example of the invention is the use of a succinate salt of thecompound of formula (Is) or a product prepared according to any of theprocesses described herein in the preparation of a medicament fortreating: (a) a sleep/wake disorder, (b) an arousal/vigilance disorders,(c) insomnia, (d) jet lag, (e) attention deficit hyperactivity disorders(ADHD), (f) a learning disorder, (g) a memory disorder, (h) cognitivedysfunction, (i) migraine, (j) neurogenic inflammation, (k) dementia,(l) mild cognitive impairment (pre-dementia), (m) Alzheimer's disease,(n) epilepsy, (o) narcolepsy, (p) an eating disorder, (q) obesity, (r)motion sickness, (s) vertigo, (t) schizophrenia, (u) substance abuse,(v) bipolar disorder, (w) manic disorder, (x) depression, (y) upperairway allergic response, (z) asthma, (aa) itch, (bb) nasal congestionor (cc) allergic rhinitis, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to processes for the preparation ofcompounds of formula (I)

wherein n, R¹, R², R³, m and Q are as herein defined, useful for thetreatment of disorders and conditions modulated by a histamine receptor.

As used herein, “C_(a-b)” (where a and b are integers) refers to aradical containing from a to b carbon atoms inclusive. For example, C₁₃denotes a radical containing 1, 2 or 3 carbon atoms.

As used herein, “halo” or “halogen” shall mean monovalent radicals ofchlorine, bromine, fluorine and iodine.

As used herein, the term “alkyl”, whether used alone or as part of asubstituent group, shall include straight and branched saturated carbonchains. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.Unless otherwise noted, “lower” when used with alkyl means a carbonchain composition of 1-4 carbon atoms. “Alkylene” refers to a bivalenthydrocarbyl group, such as methylene (—CH₂—), ethylene (—CH₂—CH₂—) orpropylene (—CH₂CH₂CH₂—), and so on.

As used herein, the term “alkylene” refers to a divalent straight- orbranched-chain alkyl group. Suitable examples include, but are notlimited to methylene, ethylene, n-propylene, and the like.

As used herein, unless otherwise noted, “alkenyl” shall mean an alkylenegroup with at least two hydrogen atoms replaced with a pi bond to form acarbon-carbon double bond, such as propenyl, butenyl, pentenyl, and soon. Where the alkenyl group is R⁸ or R⁹, the open radical (point ofattachment to the rest of the molecule) is on Sp³ carbon, as illustratedby allyl, and the double bond or bonds is therefore at least alpha (ifnot beta, gamma, etc.) to the open radical.

As used herein, “alkylidene” refers to a saturated or unsaturated,branched, straight-chain or cyclic divalent hydrocarbon radical derivedby removal of two hydrogen atoms from the same carbon atom of a parentalkane, alkene or alkyne. The divalent radical center forms a doublebond with a single atom on the rest of the molecule. Typical alkylideneradicals include, but are not limited to, ethanylidene; propylidenessuch as propan-1-ylidene, propan-2-ylidene, cyclopropan-1-ylidene;butylidenes such as butan-1-ylidene, butan-2-ylidene,2-methyl-propan-1-ylidene, cyclobutan-1-ylidene; and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above-described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “cycloalkyl” shall denote athree- to eight-membered, saturated monocyclic carbocyclic ringstructure. Suitable examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, unless otherwise noted, “cycloalkenyl” shall denote athree- to eight-membered, partially unsaturated, monocyclic, carbocyclicring structure, wherein the ring structure contains at least one doublebond. Suitable examples include cyclohexenyl, cyclopentenyl,cycloheptenyl, cyclooctenyl, cyclohex-1,3-dienyl and the like.

As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.Divalent radicals include phenylene (—C₆H₄—) which is preferablyphen-1,4-diyl, but may also be phen-1,3-diyl.

As used herein, unless otherwise noted, “aralkyl” shall mean any alkylgroup substituted with an aryl group such as phenyl, naphthyl, and thelike. Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.

As used herein, unless otherwise noted, “carbocyclyI” shall mean anycyclic group consisting of 3-12 carbon atoms, and preferably 6-9 carbonatoms, in the skeleton ring or rings, if the carbocycle is a fused orspiro bicyclic or tricyclic group. A carbocycle may be saturated,unsaturated, partially unsaturated, or aromatic. Examples includecycloalkyl, cycloalkenyl, cycloalkynyl; specific examples includephenyl, benzyl, indanyl, and biphenyl. A carbocycle may havesubstituents that are not carbon or hydrogen, such as hydroxy, halo,halomethyl, and so on as provided elsewhere herein.

As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyI” and “heterocyclo” shall denote any three-, four-, five-,six-, seven-, or eight-membered monocyclic, nine- or ten-memberedbicyclic, or thirteen- or fourteen-membered tricyclic ring structurecontaining at least one heteroatom moiety selected from the groupconsisting of NH, O, SO, SO₂, (C═O), and S, and preferably NH, O, or S,optionally containing one to four additional heteroatoms in each ring.In some embodiments, the heterocyclyl contains between 1 and 3 orbetween 1 and 2 additional heteroatoms. Unless otherwise specified, aheterocyclyl may be saturated, partially unsaturated, aromatic orpartially aromatic. The heterocyclyl group may be attached at anyheteroatom or carbon atom that results in the creation of a stablestructure.

Exemplary monocyclic heterocyclic groups can include pyrrolidinyl,pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl,4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, triazolyl, tetrazolyl, azetidinyl and the like.

For example, where Q is a saturated 3-12 membered N-linked heterocyclyl,Q necessarily contains at least one nitrogen, and the carbon atoms aresp³ hybridized. Where Q is a fused bicyclic heterocyclyl, the carbonatoms of the ring linked to L is sp³ hybridized, provided the adjacentring (and the common carbon atoms) may be sp², such as an indanyl whereone of the carbon atoms has been replaced with nitrogen.

In general, exemplary bicyclic heterocyclyls include benzthiazolyl,benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl,furopyridinyl (such as furo{2,3-c}pyridinyl, furo{3,1-b}pyridinyl), orfuro{2,3-b}pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (suchas 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl,

and the like.

Exemplary tricyclic heterocylclic groups include acridinyl,phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl,phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.

Preferred heterocyclyl groups include morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl,hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,1,3,4-trihydroisoquinolinyl, 4,5,6,7-tetrahydroindadolyl, benzoxazinyl,benzoaxzolyl, benzthiazolyl, benzimidazolyl, tetrazolyl, oxadiazolyl,

As used herein, unless otherwise noted, the term “heterocyclyl-alkyl” or“heterocyclyI-alkylene” shall denote any alkyl group substituted with aheterocyclyl group, wherein the heterocycly-alkyl group is bound throughthe alkyl portion to the central part of the molecule. Suitable examplesof heterocyclyl-alkyl groups include, but are not limited topiperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl,piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl, pyridylmethyl,pyrimidylethyl, and the like.

When a particular group is “substituted” (e.g., alkyl, alkylene,cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula

Unless otherwise noted, the position on the core phenyl ring of thecompounds of formula (I) to which the R², R³ and —(CH₂)_(m)-Qsubstituent groups are bound shall be defined as numbered in a clockwisedirection around the phenyl ring, beginning with the carbon atom towhich the —C(O)— group is bound, as drawn below

In the compounds of formula (I) of the present invention, R², R³ and—(CH₂)_(m)-Q may be bound at the 2-, 3- and/or 4- positions only.Further, the 5- and 6-positions are unsubstituted. Thus, in thecompounds of formula (I), the positions to which R², R³ and —(CH₂)_(m)-Qare bound may be as listed below: 2-position 3-position 4-position R² R³—(CH₂)_(m)-Q R³ R² —(CH₂)_(m)-Q R² —(CH₂)_(m)-Q R³ R³ —(CH₂)_(m)-Q R²—(CH₂)_(m)-Q R² R³ —(CH₂)_(m)-Q R³ R²

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes prevention, inhibition of onset, oralleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Abbreviations used in the specification, particularly in the Schemes andExamples, are as follows:

CDI=N,N′-Carbonyldiimidazole

DCM=Dichloromethane

DIPEA=Diisopropyl ethyl amine

DMF=Dimethylformamide

DSC Differential Scanning Calorimetry

DVS=Dynamic Vapour Sorption

EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

Et₂O=Diethyl Ether

EtOAc=Ethyl Acetate

EtOH=Ethanol

HOBt=1-Hydroxybenzotriazole

HPLC=High Performance Liquid Chromatography

MeOH=Methanol

MTBE=Methyl t-Butyl Ether

NaBH(OAc)₃=Sodium triacetoxyborohydride

NMR=Nuclear Magnetic Resonance

OBt=—O—(1-benzotriazolyl)

RH=Relative Humidity

TEA or Et₃N=Triethylamine

THF=Tetrahydrofuran

TLC=Thin Layer Chromatography

XRD X-Ray Diffraction

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, imidazolyl, and the like.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similalry, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art. For example, one skilled in the art will recognizethat in the processes of the present invention, it may be necessaryand/or desirable to protect substituent groups such as(C₁₋₈alkylcarbonyl)C₁₋₈alkyl.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino) -ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) wherein R¹ is selected from thegroup consisting of C₁₋₆alkyl (preferably isopropyl) and C₃₋₈cycloalkyl(preferably cyclopropyl or cyclobutyl); n is 1; R² and R³ are eachhydrogen; R⁴ is —(CH₂)-Q; and Q is a 5- to 6-membered N-linkedheterocyclyl, wherein in addition to N-linking nitrogen, theheterocyclyl may optionally contain between 1 and 2 additionalheteroatoms independently selected form O, S and NH.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) wherein:

(a) n is 1;

(b) R¹ is C₁₋₁₀ alkyl (preferably branched);

(c) R¹ is branched C₃₋₅ alkyl;

(d) one of R², R³ and R⁴ is G; (preferably one of R³ and R⁴ is G)

(e) R⁴ is G;

(f) L is unbranched —(CH₂)_(m)—, wherein m is an integer from 1 to 4;

(g) L is —CH₂—;

(h) Q is a saturated N-linked nitrogen-containing heterocyclyl;

(i) Q is substituted or unsubstituted piperidinyl, diazepanyl, azepanyl,decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pyrrolidinyl,thiomorpholinyl, or morpholinyl;

(j) Q is unsubstituted diazepanyl, azepanyl, morpholinyl,decahydroisoquinolin-2-yl, piperidinyl, or pyrrolidinyl;

(k) substituted Q are selected from N-(C₁₋₆ alkyl)piperazinyl,N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and1,4-dioxa-8-aza-spiro{4.5}decyl;

(I) Q is a monovalent radical of an amine selected from aziridine,1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylicacid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, and pyridin-2-ylamine;

(m) Q is selected from diazepanyl, azepanyl, morpholinyl, piperidinyl,and pyrrolidinyl, optionally substituted with between 1 and 3substituents independently selected from hydroxy, halo, carboxamide,C₁₋₆ alkyl, 5-9 membered or 6-9 membered heterocyclyl, —N(C₁₋₆alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9 membered or6-9 membered heterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9membered or 6-9 membered heterocyclyl)C₁₋₃ alkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl)—O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene—O—, where each of above heterocyclyl, phenyl, and alkyl groupsmay be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, methoxy, halo, nitro,cyano, hydroxy, and C₁₋₃ alkyl;

(n) Q is substituted with a substituent comprising a 5-9 membered or 6-9membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl,thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl,2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,(tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,triazolyl, (pyrrolyl)C₁₋₆ alkylene, pyrrolidinyl, and pyrrolyl;

(o) Q is piperidinyl;

(p) R⁸ is hydrogen;

(q) R⁹ is C₁₋₆ alkyl;

(r) R⁹ is unsubstituted or substituted phenyl;

(s) R⁸ and R⁹ independently are C₁₋₆ alkyl;

(t) R⁸ and R⁹ are methyl;

(u) R⁸ and R⁹ are ethyl;

(v) R⁹ is selected from phenyl or 5-9 membered aromatic heterocyclyl,wherein said phenyl or aromatic heterocyclyl is optionally substitutedwith 1-3 substituents selected from methoxy, hydroxy, halo, nitro,cyano, trifluoromethyl, and C₁₋₃ alkyl;

(w) R⁹ is selected from substituted or unsubstituted phenyl, pyridyl,pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene,oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆ alkylene,pyrrolidinyl, and pyrrolyl;

(x) R⁹ is substituted or unsubstituted pyridyl;

(y) X is O; and

(z) combinations of (a) through (z) above.

In another embodiment, the present invention is directed to processesfor the preparation of compounds of formula (I) selected from the groupconsisting of:

-   (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-yl    methyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone;-   (4-Butyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {3-(4-Benzyl-piperidin-1-ylmethyl)-phenyl}-(4-methyl-piperazin-1-yl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-phenylaminomethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifl uoromethyl-piperid    in-1-yl methyl) -phenyl}-methanone dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;    and-   {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride.

Preferably, the processes of the present invention are directed tomaking compounds selected from the group consisting of:

-   (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-yl    methyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;

(4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanonedihydrochloride;

-   (4-Isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifl uoromethyl-piperid    in-1-yl methyl) -phenyl}-methanone dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;-   {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;    and-   {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride.

Preferably, the present invention is directed to processes for thepreparation of a compound of formula (I) selected from the groupconsisting of:

-   (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-yl    methyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifl uoromethyl-piperid    in-1-yl methyl)-phenyl}-methanone dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;-   {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride; and-   {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone.

More preferably, the present invention is directed to processes for thepreparation of a compound of formula (I) selected from the groupconsisting of:

-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;    and-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone.

More preferably still, the present invention is directed to processesfor the preparation of a compound of formula (I) selected from the groupconsisting of:

-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride; and-   {4-(l    -Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride.

The present invention is directed to a process for the preparation ofcompounds of formula (I). The process of the present invention isadvantageous for large scale and/or commercial purposes because it doesnot require isolation and/or purification of oily intermediates; anddoes not require column chromatography which is impractical and highlycost prohibitive on a large and/or commercial scale. Additionally, theprocess of the present invention may be completed in a single solventsystem, whereas the process as disclosed in US Patent ApplicationPublication 2004-0010746 A1, published Apr. 21, 2005 (also published asPCT Publication WO 2004/037801, May 6, 2004) requires multiple solvents(including reaction and extractive work-up solvents).

The present invention is directed to a process for the preparation ofcompounds of formula (I), as described in more detail in Scheme 1 below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is activated accordingto known methods, in a first organic solvent; to yield the correspondingcompound of formula (XI), wherein L is a suitable leaving group such aschloro, bromo, —OC(O)O—C₁₋₄alkyl, OBt (wherein the activating agent isHOBt), -imidazolide (wherein the activating agent is CDI), and the like;preferably chloro.

For example, wherein L is chloro, the compound of formula (X) is reactedwith a suitable chlorinating agent such as oxalyl chloride, thionylchloride, phosphorus oxychloride, and the like, preferably about 1.05equivalents of oxalyl chloride in the presence of a catalytic amount ofDMF; in an organic solvent such as THF, toluene, dichloromethane,dichloroethane, acetonitrile, and the like, preferably THF.Alternatively, the compound of formula (X) is reacted with Vilsmeier'sreagent (chloromethylene-dimethyl-ammonium chloride) in an organicsolvent such as DCM; at a temperature in the range of from about 0° C.to about room temperature.

The compound of formula (XI) is not isolated.

The compound of formula (XI) is reacted with a suitably substitutedcompound of formula (XII), a known compound or compound prepared byknown methods, wherein the compound of formula (XII) is preferablypresent in an amount equal to about one equivalent, more preferablyabout 0.95 equivalents; in the presence of an organic or inorganic base(solid or aqueous) such as TEA, DIPEA, pyridine, NaOH, KOH, sodiumcarbonate, potassium carbonate, and the like, preferably 50% aqueousNaOH; wherein the base is organic, preferably in the absence of water;in a second organic solvent such as THF, toluene, acetonitrile, and thelike, preferably THF; to yield the corresponding compound of formula(XIII).

The compound of formula (XIII) is not isolated.

The compound of formula (XIII) is reacted with a suitably substitutedcompound of formula (XIV), a known compound or compound prepared byknown methods, wherein the compound of formula (XIV) is preferablypresent in an amount greater than about one equivalent, more preferablyin an amount in the range of from about 1 to about 5 equivalents, morepreferably still in an amount in the range of from about 1.5 to about2.5 equivalents, most preferably in an amount in the range of from about1.5 to about 2 equivalents; in the presence of a reducing agent such asNaBH(OAc)₃, NaBH₄, sodium cyanoborohydride, and the like, preferably,NaBH(OAc)₃; wherein the reducing agent is preferably present in anamount in the range of from about 1 to about 2 equivalents, morepreferably in an amount in the range of from about 1.25 to about 1.5equivalents; in a third organic solvent such as THF, toluene,acetonitrile, and the like, preferably, THF; to yield the correspondingcompound of formula (I).

Preferably, the compound of formula (I) is not isolated and/or purified.More preferably, the compound of formula (I) is reacted according toknown methods, to yield a corresponding pharmaceutically acceptable saltof the compound of formula (I). Optionally, the compound of formula (I)is isolated and/or purified according to known methods.

Preferably, the first organic solvent, the second organic solvent andthe third organic solvent are the same. Preferably, the conversion ofthe compound of formula (X) to the corresponding compound of formula (I)is completed in a single solvent system.

In an embodiment of the present invention, the compound of formula (I)is further reacted with a suitably selected pharmaceutically acceptableacid to yield the corresponding pharmaceutically acceptable salt of thecompound of formula (I). In an embodiment of the present invention, thecompound of formula (I) is not isolated and is reacted with a suitablyselected pharmaceutically acceptable acid to yield the correspondingpharmaceutically acceptable salt of the compound of formula (I).

One skilled in the art will recognize that in the synthesis of compoundsof formula (I) wherein the —(CH₂)_(m)-Q substituent group is bound tothe 2-position on the phenyl ring, the aldehyde on the compound offormula (X) is preferably protected, with a suitable protecting groupsaccording to known methods, until after the reaction with the compoundof formula (XII) and then de-protected to react with the compound offormula (XIV).

In an embodiment, the present invention is directed to a process for thepreparation of the compound of formula (Is), also known as (4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone, as describedin more detail in Scheme 2 below.

Accordingly, a suitably substituted compound of formula (Xs), also knownas 4-formyl-benzoic acid, a known compound, is activated according toknown methods, in a first organic solvent, to yield the correspondingcompound of formula (XIs), wherein L is a suitable leaving group such aschloro, bromo, —OC(O)O—C₁₋₄alkyl, OBt (wherein the activating agent isHOBt), -imidazolide (wherein the activating agent is CDI), and the like;preferably chloro.

For example, wherein L is chloro, the compound of formula (Xs) isreacted with a suitable chlorinating agent such as oxalyl chloride,thionyl chloride, phosphorus oxychloride, and the like, preferably about1.05 equivalents of oxalyl chloride in the presence of a catalyticamount of DMF; in an organic solvent such as THF, toluene,dichloromethane, dichloroethane, acetonitrile, and the like, preferablyTHF. Alternatively, the compound of formula (Xs) is reacted withVilsmeier's reagent (chloromethylene-dimethyl-ammonium chloride) in anorganic solvent such as DCM; at a temperature in the range of from about0° C. to about room temperature.

The compound of formula (XIs) is not isolated.

The compound of formula (XIs) is reacted with a suitably substitutedcompound of formula (XIIs), also known as N-isopropylpiperazine, a knowncompound; wherein the compound of formula (XIIs) is preferably presentin an amount equal to about one equivalent, more preferably about 0.95equivalents; in the presence of an organic or inorganic base (solid oraqueous) such as TEA, DIPEA, pyridine, NaOH, KOH, sodium carbonate,potassium carbonate, and the like, preferably 50% aqueous NaOH; whereinthe base is organic, preferably in the absence of water; in a secondorganic solvent such as THF, toluene, acetonitrile, and the like,preferably THF; to yield the corresponding compound of formula (XIIIs),also known as 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde.

The compound of formula (XIIIs) is not isolated.

The compound of formula (XIIIs) is reacted with a suitably substitutedcompound of formula (XIVs), also known as morpholine, a known compound,wherein the compound of formula (XIVs) is preferably present in anamount greater than about one equivalent, more preferably in an amountin the range of from about 1 to about 5 equivalents, more preferablystill in an amount in the range of from about 1.5 to about 2.5equivalents, most preferably in an amount in the range of from about 1.5to about 2 equivalents; in the presence of a reducing agent such asNaBH(OAc)₃, NaBH₄, sodium cyanoborohydride, and the like, preferably,NaBH(OAc)₃; wherein the reducing agent is preferably present in anamount in the range of from about 1 to about 2 equivalents, morepreferably in an amount in the range of from about 1.25 to about 1.5equivalents; in a third organic solvent such as THF, toluene,acetonitrile, and the like, preferably, THF; to yield the correspondingcompound of formula (Is), also known as(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.

Preferably, the compound of formula (Is) is not isolated and/orpurified. More preferably, the compound of formula (Is) is reacted,according to known methods, to yield a corresponding pharmaceuticallyacceptable salt of the compound of formula (Is), more preferably stillthe mono-succinate salt of the compound of formula (Is). Optionally, thecompound of formula (Is) is isolated and/or purified according to knownmethods.

In an embodiment of the present invention, the compound of formula (Is)is further reacted with a suitably selected pharmaceutically acceptableacid to yield the corresponding pharmaceutically acceptable salt of thecompound of formula (Is). In an embodiment of the present invention, thecompound of formula (Is) is not isolated and is reacted with a suitablyselected pharmaceutically acceptable acid to yield the correspondingpharmaceutically acceptable salt of the compound of formula (Is).

US Patent Application Publication 2004-0010746 A1, published Apr. 21,2005 (also published as PCT Publication WO 2004/037801, May 6, 2004)discloses a process for the preparation of the compounds of formula (I).In an embodiment, the present invention is directed to improvements inthe process for the preparation of the compounds of formula (I) asdisclosed in US Patent Application Publication 2004-0010746 A1.

More specifically, the improvements of the present invention are thepreparation of a bisulfite intermediate (a compound of formula (XVII))in the Schemes which follow herein) which may be isolated as a solid,thereby providing an improved means of purification (in the processdisclosed in US Patent Application Publication 2004-0010746 A1 thealdehyde intermediate of formula (XIII) is isolated as an oil and thenpurified by column chromatography). Additionally, the bisulfiteintermediate provides improved stability and shelf-life relative to thealdehyde intermediate.

In an embodiment, the present invention is directed to a process for thepurification of the aldehyde intermediate, a compound of formula (XII),comprising preparation of its corresponding bisulfite derivative,isolation of said bisulfite derivative as a solid, by for examplefiltration, and optionally purification according to known methods, forexample by recrystallization from a suitable solvent such as methanol,ethanol, isopropanol, acetonitrile, and the like, preferably ethanol.The bi-sulfite derivative may then be further reacted as describedherein to yield the desired compound of formula (I) or alternatively,may be reacted to re-form the compound of formula (XIII), which is thenreacted according to the processes as described herein, to yield thedesired compound of formula (I).

The improved process of the present invention is as described in moredetail in Scheme 3 below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is activated accordingto known methods, to yield the corresponding compound of formula (XI),wherein L is a suitable leaving group such as chloro, bromo,—OC(O)O—C₁₋₄alkyl, OBt (wherein the activating agent is HOBt),-imidazolide (wherein the activating agent is CDI), and the like;preferably chloro.

For example, wherein L is chloro, the compound of formula (X) is reactedwith a suitable chlorinating agent such as oxalyl chloride, thionylchloride, phosphorus oxychloride, and the like, preferably about 1.05equivalents of thionyl chloride in the presence of a catalytic amount ofDMF; in an organic solvent such as THF, toluene, dichloromethane,dichloroethane, acetonitrile, and the like, preferably THF.Alternatively, the compound of formula (X) is reacted with Vilsmeier'sreagent (chloromethylene-dimethyl-ammonium chloride) in an organicsolvent such as DCM; at a temperature in the range of from about 0° C.to about room temperature.

Preferably, the compound of formula (XI) is not isolated.

The compound of formula (XI) is reacted with a suitably substitutedcompound of formula (XII), a known compound or compound prepared byknown methods, wherein the compound of formula (XII) is preferablypresent in an amount equal to about one equivalent, more preferablyabout 0.95 equivalents; in the presence of an organic or inorganic base(solid or aqueous) such as TEA, DIPEA, pyridine, NaOH, KOH, sodiumcarbonate, potassium carbonate, and the like, preferably TEA; whereinthe base is organic, preferably in the absence of water; in an organicsolvent such as THF, toluene, acetonitrile, and the like, preferablyTHF; to yield the corresponding compound of formula (XIII).

Preferably, the compound of formula (XIII) is not isolated.

The compound of formula (XIII) is reacted with a suitable source ofbisulfite such as NaHSO₃, KHSO₃, and the like, preferably aqueousNaHSO₃; wherein the source of bisulfite is preferably present in anamount greater than or equal to about one equivalent, more preferably inan amount in range of from about 1 to about 2 equivalents, morepreferably still in an amount equal to about 1.2 equivalents; in a polarorganic solvent such as methanol, ethanol, THF, DMF, acetonitrile, andthe like, preferably ethanol; to yield the corresponding bisulfite, thecompound of formula (XVII).

Preferably, the compound of formula (XVII) is isolated by known methods,for example by filtration and washing with a suitable organic solventsuch ethanol, hexane, and the like; and then further, optionallypurified, by known methods, for example by recrystallization from asuitable solvent such as methanol, ethanol, isopropanol, acetonitrile,and the like, preferably ethanol.

The compound of formula (XVII) is reacted in a 2-step or 1-step process,wherein the bisulfite is reacted to liberate the corresponding aldehyde,the compound of formula (XIII) and the aldehyde compound of formula(XIII) is reacted with the compound of formula (XIV) to yield thecorresponding compound of formula (I).

More specifically, the compound of formula (XVII) is reacted with asuitably substituted compound of formula (XIV), a known compound orcompound prepared by known methods, wherein the compound of formula(XIV) is preferably present in an amount greater than about oneequivalent, more preferably in an amount in the range of from about 1 toabout 2 equivalents; more preferably still, about 2 equivalents; in thepresence of a reducing agent such as NaBH(OAc)₃, NaBH₄, sodiumcyanoborohydride, and the like, preferably, NaBH(OAc)₃; wherein thereducing agent is preferably present in an amount in the range of fromabout 1 to about 2 equivalents, more preferably in an amount in therange of from about 1.25 to about 1.5 equivalents; in the presence of anorganic or inorganic base such as TEA, DIPEA, pyridine, NaOH, KOH, andthe like, preferably 10% aqueous NaOH; in an organic solvent such asdichloroethane, THF, toluene, acetonitrile, and the like, preferably,dichloroethane; optionally in the presence of a source of acid such asthe acid clay Montmorillonite K-10 (available from Aldrich), Nafion-H(CA Reg. No. 63937-00-8), and the like; to yield the correspondingcompound of formula (I).

One skilled in the art will recognize that wherein the amount of thecompound of formula (XIV) is greater than or equal to about 2equivalents, then one equivalent of the compound of formula (XIV) actsas the organic or inorganic base to liberate the aldehyde, the compoundof formula (XIII) and therefore, additional organic or inorganic base isnot necessary.

Alternatively, the compound of formula (XVII) is reacted with an organicor inorganic base such as TEA, DIPEA, pyridine, NaOH, KOH, and the like,preferably 10% aqueous NaOH; wherein the base is preferably present inan amount greater than or equal to about 1 equivalent, more preferablyin an amount in the range of from about 1 to about 2 equivalents;according to known methods to remove the bisulfite and liberate thecorresponding compound of formula (XIII).

The compound of formula (XIII) is then reacted with a suitablysubstituted compound of formula (XIV), wherein the compound of formula(XIV) is preferably present in an amount greater than or equal to about1 equivalent, preferably in an amount in the range of form about 1 toabout 2 equivalents; in the presence of a reducing agent such asNaBH(OAc)₃, NaBH₄, sodium cyanoborohydride, and the like, preferably,NaBH(OAc)₃; wherein the reducing agent is preferably present in anamount in the range of from about 1 to about 2 equivalents, morepreferably in an amount in the range of from about 1.25 to about 1.5equivalents; optionally in the presence of a source of acid such as theacid clay Montmorillonite K-10 (available from Aldrich), Nafion-H (CAReg. No. 63937-00-8), and the like; in an organic solvent such as THF,toluene, acetonitrile, and the like, preferably, THF; to yield thecorresponidng compound of formula (I).

Alternatively, the compound of formula (XIII) is reacted with a suitablysubstituted compound of formula (XIV) according to the methods asdescribed herein or as described in US Patent Application Publication2004-0010746 A1, to yield the corresponding compound of formula (I).

Preferably, the compound of formula (I) is isolated according to knownmethods, for example by solvent evaporation. The compound of formula (I)may be further, optionally, reacted according to known methods, to yieldits corresponding pharmaceutically acceptable salt.

In an embodiment, the present invention is directed to improvements inthe process disclosed in US Patent Application Publication 2004-0010746A1 for the preparation of the compound of formula (Is), also known as(4-isopropyl -piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,as described in more detail in Scheme 4 below.

Accordingly, a suitably substituted compound of formula (Xs), also knownas 4-formyl-benzaldehyde, a known compound, is activated according toknown methods, to yield the corresponding compound of formula (XIs),wherein L is a suitable leaving group such as chloro, bromo,—OC(O)O—C₁₋₄alkyl, OBt (wherein the activating agent is HOBt),-imidazolide (wherein the activating agent is CDI), and the like;preferably chloro.

For example, wherein L is chloro, the compound of formula (Xs) isreacted with a suitable chlorinating agent such as oxalyl chloride,thionyl chloride, phosphorus oxychloride, and the like, preferably about1.05 equivalents of thionyl chloride in the presence of a catalyticamount of DMF in an organic solvent such as THF, toluene,dichloromethane, dichloroethane, acetonitrile, and the like, preferablyTHF. Alternatively, the compound of formula (Xs) is reacted withVilsmeier's reagent (chloromethylene-dimethyl-ammonium chloride) in anorganic solvent such as DCM; at a temperature in the range of from about0° C. to about room temperature.

Preferably, the compound of formula (XIs) is not isolated.

The compound of formula (XIs) is reacted with a suitably substitutedcompound of formula (XIIs), also known as 4-isopropylpiperazine, a knowncompound, wherein the compound of formula (XIIs) is preferably presentin an amount equal to about one equivalent, more preferably about 0.95equivalents; in the presence of an organic or inorganic base (solid oraqueous) such as TEA, DIPEA, pyridine, NaOH, KOH, sodium carbonate,potassium carbonate, and the like, preferably TEA; wherein the base isorganic, preferably in the absence of water; in an organic solvent suchas THF, toluene, acetonitrile, and the like, preferably THF; to yieldthe corresponding compound of formula (XIIIs).

Preferably, the compound of formula (XIIIs) is not isolated.

The compound of formula (XIIIs) is reacted with a suitable source ofbisulfite such as NaHSO₃, KHSO₃, and the like, preferably aqueousNaHSO₃; wherein the source of bisulfite is preferably present in anamount greater than or equal to about one equivalent, more preferably inan amount in range of from about 1 to about 2 equivalents, morepreferably still in an amount equal to about 1.2 equivalents; in a polarorganic solvent such as methanol, ethanol, THF, DMF, acetonitrile, andthe like, preferably ethanol; to yield the corresponding bisulfite, thecompound of formula (XVIIs).

Preferably, the compound of formula (XVIIs) is isolated by knownmethods, for example by filtration and washing with a suitable organicsolvent such ethanol, hexane, and the like; and then further, optionallypurified, by known methods, for example by recrystallization from asuitable solvent such as methanol, ethanol, isopropanol, acetonitrile,and the like, preferably ethanol.

The compound of formula (XVIIs) is reacted in a 2-step or 1-stepprocess, wherein the bisulfite is reacted to liberate the correspondingaldehyde, the compound of formula (XIIIs) and the aldehyde compound offormula (XIIIs) is reacted with the compound of formula (XIVS) to yieldthe corresponding compound of formula (Is).

More specifically, the compound of formula (XVIIs) is reacted with asuitably substituted compound of formula (XIVs), also known asmorpholine, a known compound, wherein the compound of formula (XIVs) ispreferably present in an amount greater than about one equivalent, morepreferably in an amount in the range of from about 1 to about 2equivalents; more preferably still, about 2 equivalents; in the presenceof a reducing agent such as NaBH(OAc)₃, NaBH₄, sodium cyanoborohydride,and the like, preferably, NaBH(OAc)₃; wherein the reducing agent ispreferably present in an amount in the range of from about 1 to about 2equivalents, more preferably in an amount in the range of from about1.25 to about 1.5 equivalents; in the presence of an organic orinorganic base such as TEA, DIPEA, pyridine, NaOH, KOH, and the like,preferably 10% aqueous NaOH; in an organic solvent such asdichloroethane, THF, toluene, acetonitrile, and the like, preferably,dichloroethane; optionally in the presence of a source of acid such asthe acid clay Montmorillonite K-10 (available from Aldrich), Nafion-H(CA Reg. No. 63937-00-8), and the like; to yield the correspondingcompound of formula (Is).

One skilled in the art will recognize that wherein the amount of thecompound of formula (XIVs) is greater than or equal to about 2equivalents, then one equivalent of the compound of formula (XIVs) actsas the organic or inorganic base to liberate the aldehyde, the compoundof formula (XIIIs) and therefore, additional organic or inorganic baseis not necessary.

Alternatively, the compound of formula (XVIIs) is reacted with anorganic or inorganic base such as TEA, DIPEA, pyridine, NaOH, KOH, andthe like, preferably 10% aqueous NaOH; wherein the base is preferablypresent in an amount greater than or equal to about 1 equivalent, morepreferably in an amount in the range of from about 1 to about 2equivalents; according to known methods to remove the bisulfite andliberate the corresponding compound of formula (XIIIs).

The compound of formula (XIIs) is then reacted with a suitablysubstituted compound of formula (XIVs), wherein the compound of formula(XIVs) is preferably present in an amount greater than or equal to about1 equivalent, preferably in an amount in the range of form about 1equivalent to about 2 equivalents; in the presence of a reducing agentsuch as NaBH(OAc)₃, NaBH₄, sodium cyanoborohydride, and the like,preferably, NaBH(OAc)₃; wherein the reducing agent is preferably presentin an amount in the range of from about 1 to about 2 equivalents, morepreferably in an amount in the range of from about 1.25 to about 1.5equivalents; optionally in the presence of a source of acid such as theacid clay Montmorillonite K-10 (available from Aldrich), Nafion-H (CAReg. No. 63937-00-8), and the like; in an organic solvent such as THF,toluene, acetonitrile, and the like, preferably, THF; to yield thecorresponidng compound of formula (Is).

Alternatively, the compound of formula (XIIIs) is reacted with asuitably substituted compound of formula (XIVs) according to the methodsas described herein or as described in US Patent Application Publication2004-0010746 A1, to yield the corresponding compound of formula (Is).

Preferably, the compound of formula (Is) is isolated according to knownmethods, for example by solvent evaporation. The compound of formula(Is) may be further, optionally, reacted according to known methods, toyield its corresponding pharmaceutically acceptable salt, preferably,its corresponding mono-succinate salt.

The present invention is further directed to novel crystalline salts ofthe compound of formula (I). In an embodiment, the present invention isdirected to a maleate, fumarate, succinate, hydrochloride orhydrobromide salt of the compound of formula (I).

The present invention is further directed to novel crystalline salts ofthe compound of formula (Is). In an embodiment, the present invention isdirected to a maleate, fumarate, succinate, hydrochloride orhydrobromide salt of the compound of formula (Is).

In an embodiment, the present invention is directed to a crystallinesuccinate salt of the compound of formula (Is). In another embodiment,the crystalline succinate salt of the compound of formula (Is) is amono-succinate salt. The crystalline mono-succinate salt of the compoundof formula (Is) is non-hygroscopic. The mono-succinate salt of thecompound of formula (Is) was determined to be crystalline by XRD andDSC; and non-hygroscopic by DVS.

The crystalline mono-succinate salt of the compound of formula (Is) maybe represented by the following chemical structure:

The crystalline succinate salt of the compound of formula (Is) may beprepared by reacting the compound of formula (Is) with succinic acid;wherein the succinic acid is preferably present in an amount in therange of from about 1 to about 2 equivalents, more preferably about 1.3equivalents; in an organic solvent such as THF, toluene, acetonitrile,and the like, preferably in an organic solvent in which succinic acid issoluble, more preferably in THF.

The crystalline succinate salt of the compound of formula (Is) ispreferably purified according to known methods, more preferably byrecrystallization from a suitable solvent such as absolute ethanol,methanol, isopropyl alcohol, acetonitrile, and the like, preferably fromabsolute ethanol.

The present invention is further directed to a pharmaceuticallyacceptable salt of the compound of formula (Is) wherein the salt is amaleate, fumarate, hydrochloride or hydrobromide salt of the compound offormula (Is). In another embodiment, the salt of the compound of formula(Is) is a bis-maleate, mono-fumarate, di-hydrochloride ordi-hydrobromide salts of the compound of formula (Is). The bis-maleate,mono-fumarate, di-hydrochloride and di-hydrobromide salts of thecompound of formula (Is) may be prepared by reacting the compound offormula (Is) with the corresponding acid (i.e. maleic acid, fumaricacid, HCl and HBr, respectively), as described in more detail in theExamples which follow herein.

The bis-maleate salt of the compound of formula (Is) was determined tobe crystalline by XRD and DSC; and hygroscopic by DVS. The fumarate saltof the compound of formula (Is) was determined to be crystalline by XRDand DSC; and stable at relative humidities of up to about 70% by DVS.The di-hydrochloride salt of the compound of formula (Is) was determinedto be partially crystalline by XRD and DSC; and a mono-hydrate byKarl-Fisher and hygroscopic by DVS. The di-hydrobromide salt of thecompound of formula (Is) was determined to be partially crystalline byXRD and DSC; a semi-hydrate by Karl-Fisher; and hygroscopic above about10% RH by DVS.

The salts of the compound of formula (Is) may be characterized by theircorresponding powder X-ray diffraction pattern. The X-ray diffractionpatterns listed herein were measured using an X-Celerator detector. Thesample was backloaded into a conventional x-ray holder and scanned from3 to 35°2θ with a step size of 0.0165°2θ and a time per step of 10.16seconds. The effective scan speed was 0.2067°/s. Instrument voltage andcurrent settings were 45 kV and 40 mA.

The crystalline mono-succinate salt of the compound of formula (Is) maybe characterized by its X-ray diffraction pattern, comprising the peaksas listed in Table 1, below. TABLE 1 Position [°2θ] d-spacing [Å]Relative Intensity [%] 8.782 10.0698 100.00 13.161 6.7274 62.86 14.5876.0728 13.50 15.961 5.5527 21.15 17.308 5.1237 24.32 17.555 5.0520 46.9419.767 4.4915 22.73 20.210 4.3941 19.15 20.415 4.3503 19.40 23.8023.7383 48.59 26.429 3.3728 49.97

Preferably, the crystalline mono-succinate salt of the compound offormula (Is) is characterized by its XRD pattern which comprises peakshaving a relative intensity greater than or equal to about 25%, aslisted in Table 2 below. TABLE 2 Position [°2θ] d-spacing [Å] RelativeIntensity [%] 8.782 10.0698 100.00 13.161 6.7274 62.86 17.555 5.052046.94 23.802 3.7383 48.59 26.429 3.3728 49.97

In an embodiment, the crystalline, mono-succinate salt of the compoundof formula (Is) is characterized by the peak positions (in °2θ) in itsXRD spectra for peaks with a relative intensity greater than about 10%,preferably with a relative intensity greater than about 25%.

The crystalline mono-fumarate salt of the compound of formula (Is) maybe characterized by its X-ray diffraction pattern, comprising the peaksas listed in Table 3, below. TABLE 3 Position [°2θ] d-spacing [Å]Relative Intensity [%] 9.164 9.6501 68.78 13.652 6.4862 98.14 18.1824.8791 74.48 20.318 4.3708 24.49 22.682 3.9204 11.12 24.146 3.6859 35.4324.529 3.6293 60.71 25.361 3.5121 12.35 27.081 3.2928 85.98 27.3303.2633 100.00 28.644 3.1165 19.53 28.813 3.0986 12.99 31.889 2.806 19.7631.971 2.799 12.26

Preferably, the crystalline mono-fumarate salt of the compound offormula (Is) is characterized by its XRD pattern which comprises peakshaving a relative intensity greater than or equal to about 25%, aslisted in Table 4 below. TABLE 4 Position [°2θ] d-spacing [Å] RelativeIntensity [%] 9.164 9.6501 68.78 13.652 6.4862 98.14 18.182 4.8791 74.4824.146 3.6859 35.43 24.529 3.6293 60.71 27.081 3.2928 85.98 27.3303.2633 100.00

In an embodiment, the crystalline, mono-fumarate salt of the compound offormula (Is) is characterized by the peak positions (in °2θ) in its XRDspectra for peaks with a relative intensity greater than about 10%,preferably with a relative intensity greater than about 25%.

The crystalline di-hydrochloride salt of the compound of formula (Is)may be characterized by its X-ray diffraction pattern, comprising thepeaks as listed in Table 5, below. TABLE 5 Position [°2θ] d-spacing [Å]Relative Intensity [%] 5.648 15.6651 12.12 11.220 7.8862 27.02 15.4185.7471 23.03 15.789 5.6130 47.14 16.268 5.4485 53.50 16.726 5.3005 38.7517.268 5.1353 16.41 17.565 5.0491 21.51 17.955 4.9410 14.80 18.9004.6955 19.52 19.494 4.5536 45.87 21.809 4.0753 100.00 22.452 3.960135.06 22.894 3.8845 22.57 23.394 3.8027 29.19 24.955 3.5683 35.07 25.5443.4873 27.86 26.116 3.4122 34.92 27.902 3.1977 35.17 28.710 3.1096 16.2831.481 2.8418 31.54

Preferably, the crystalline di-hydrochloride salt of the compound offormula (Is) is characterized by its XRD pattern which comprises peakshaving a relative intensity greater than or equal to about 25%, aslisted in Table 6 below. TABLE 6 Position [°2θ] d-spacing [Å] RelativeIntensity [%] 11.220 7.8862 27.02 15.789 5.6130 47.14 16.268 5.448553.50 16.726 5.3005 38.75 19.494 4.5536 45.87 21.809 4.0753 100.0022.452 3.9601 35.06 23.394 3.8027 29.19 24.955 3.5683 35.07 25.5443.4873 27.86 26.116 3.4122 34.92 27.902 3.1977 35.17 31.481 2.8418 31.54

In an embodiment, the crystalline, di-hydrochloride salt of the compoundof formula (Is) is characterized by the peak positions (in °2θ) in itsXRD spectra for peaks with a relative intensity greater than about 10%,preferably with a relative intensity greater than about 25%.

The crystalline di-hydrobromide salt of the compound of formula (Is) maybe characterized by its X-ray diffraction pattern, comprising the peaksas listed in Table 7, below. TABLE 7 Position [°2θ] d-spacing [Å]Relative Intensity [%] 11.386 7.7720 50.80 16.194 5.4735 10.38 16.7445.2949 21.92 17.071 5.1943 39.18 18.391 4.8244 100.00 19.019 4.666539.71 20.105 4.4167 13.60 21.462 4.1404 37.22 22.641 3.9274 22.33 22.9613.8735 58.57 24.407 3.6471 29.56 24.676 3.6079 41.54 25.189 3.5356 96.5427.094 3.2912 15.39 28.080 3.1778 11.46 32.02 2.9808 12.84 30.665 2.915632.02 31.292 2.8586 29.78 31.765 2.8171 17.27

Preferably, the crystalline di-hydrobromide salt of the compound offormula (Is) is characterized by its XRD pattern which comprises peakshaving a relative intensity greater than or equal to about 25%, aslisted in Table 8 below. TABLE 8 Position [°2θ] d-spacing [Å] RelativeIntensity [%] 11.386 7.7720 50.80 17.071 5.1943 39.18 18.391 4.8244100.00 19.019 4.6665 39.71 21.462 4.1404 37.22 22.961 3.8735 58.5724.407 3.6471 29.56 24.676 3.6079 41.54 25.189 3.5356 96.54 30.6652.9156 32.02 31.292 2.8586 29.78

In an embodiment, the crystalline, di-hydrobromide salt of the compoundof formula (Is) is characterized by the peak positions (in °2θ) in itsXRD spectra for peaks with a relative intensity greater than about 10%,preferably with a relative intensity greater than about 25%.

The compounds or compositions of the invention may be formulated andadministered to a subject by any conventional route of administration,including, but not limited to, intravenous, oral, subcutaneous,intramuscular, intradermal and parenteral administration. The quantityof the compound which is effective for treating each condition may vary,and can be determined by one of ordinary skill in the art.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier and optionally additionalpharmaceutical agents such as H₁ antagonists or SSRIs (SelectiveSerotonin Reuptake Inhibitors). Preferably these compositions are inunit dosage forms such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), powders, granules, sterile parenteral solutions orsuspensions (including syrups and emulsions), metered aerosol or liquidsprays, drops, ampoules, autoinjector devices or suppositories; fororal, parenteral, intranasal, sublingual or rectal administration, orfor administration by inhalation or insufflation. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid pre-formulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these pre-formulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid pre-formulation composition is then subdivided into unit dosageforms of the type described above containing from 5 to about 1000 mg ofthe active ingredient of the present invention. Examples include 5 mg, 7mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg,and so on. The tablets or pills of the disclosed compositions can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer, which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment is required.

The daily dosage of the products may be varied over a wide range from 1to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thesubject to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.02 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.05mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

EXAMPLE 1 4-Formyl-benzoyl chloride

To a thin suspension of 4-carboxybenzaldehyde (600 g, 3.92 mol) intetrahydrofuran (2664 g, 36.57 mol) was added dimethylformadehyde (11.48g, 0.16 mol) and the reaction mixture was cooled to 0-5° C. with an icebath. The reaction mixture was then stirred at 0° C. while oxalylchloride (608.69 g, 4.70 mol) was added slowly. The reaction mixture wasstirred until it was deemed complete by ¹HNMR to yield the titlecompound. The reaction mixture was used in the next step without furthermanipulation.

¹HNMR (CDCl3): 10.15 (s, 1H), 8.35 (d, 2H), 8.05 (d, 2H)

EXAMPLE 2 4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde

A solution of 4-formyl-benzoyl chloride (2.80, 16.65 mol) (prepared asin Example 1 above) in toluene (43.3 g, 469.39 mmol) was added slowly toa solution of NaHCO₃ (0.8 g, 9.52 mmol) and 4-isopropylpiperazine (2.50g, 18.35 mmol) in water (5 g, 277 mmol) at 0° C. The reaction mixturewas vigorously stirred until the reaction was deemed complete. Thelayers were split and the toluene phase was concentrated to yield thetitle compound as a yellow oil.

¹HNMR (CDCl3): 10.15 (s, 1 H), 7.95 (d, 2H), 7.55 (d, 2H), 3.75 (br s,2H), 3.40 (br s, 2H), 2.75 (m, 1H), 2.55 (br s, 2H), 2.41 (br s, 2H),1.09 (d, 6H)

EXAMPLE 3 4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde

4-Isopropyl-piperazine (79.53 g, 0.620 mol), THF (444 g, 5.04 mol),water (36 g, 2 mol) and a 50% solution of sodium hydroxide (130.6 g,1.63 mol) were charged to a reaction vessel and cooled to 0-5° C.4-Formyl-benzoyl chloride in THF (110.08 g, 0.630 mol) was added to the4-isopropyl-piperazine reaction mixture while maintaining thetemperature below about 10° C. The resulting white suspension wasstirred at room temperature until the reaction was deemed complete.Water was added to the reaction slurry and the resulting hazy solutionwas filtered over Celite to remove insolubles. The filtered reactionsolution was settled and the water layer was removed. The product/THFlayer was dried sequentially with magnesium sulfate and molecularsieves. The product solution (KF≦0.5% ) was stored at 5° C. for usewithout further manipulations.

EXAMPLE 4(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

To a solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (4.0g, 15.38 mmol) in THF (40 mL) was added morpholine (2.9 g, 33.83 mmol),and the resulting mixture was stirred at room temperature for 1 h beforeit was cooled to 0° C. with an ice bath. The reaction mixture was thentreated with NaBH(OAc)₃ (4.56 g, 21.53 mmol) in portions over 15 min.The resulting suspension was stirred at room temperature until it wasdeemed complete by HPLC. After completion, 10% NaOH (25 mL) was addedand the reaction was vigorously agitated for 15 min. The phases wereseparated and the aqueous layer was extracted with THF (20 mL). Theorganic layers were combined, dried (MgSO₄), filtered and concentratedto yield the title compound as a yellow oil.

¹H NMR (CDCl₃): 7.36 (s, 4H), 3.79 (br s, 2H), 3.71 (t, 4H), 3.51 (s,2H), 3.44 (br s, 2H), 2.76-2.69 (m, 1H), 2.59 (br s, 2H), 2.44 (t, 6H),1.05 (d, 6H).

EXAMPLE 5(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

A THF solution of 1-(4-formylbenzoyl)-4-isopropylpiperazine (containing945 g of 1-(4-formylbenzoyl)-4-isopropylpiperazine and 3879 g of THF)was charged to a reaction vessel followed by the addition of morpholine(576.3 g, 6.55 mol). After 20 min, the reaction was cooled to about0-10° C. and sodium triacetoxyborohydride (1167.3 g, 5.23 mol) was addedin portions. Upon reaction completion, 10% sodium hydroxide solution(3623.2 mL, 9.06 mol) was added slowly and the reaction mixture wasstirred for 20 min. The layers were separated, and the aqueous layer waswashed with THF. The combined organic layers were dried over magnesiumsulfate. The dried THF solution of(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanonewas used without further manipulations.

EXAMPLE 6(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanoneMono-succinate Salt

A THF solution (278.0 g) of crude(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone(59.4 g, 0.179 mol) was heated to 40° C. and succinic acid (27.53 g,0.233 mol) was added. The reaction mixture was heated to 60° C. andfiltered into a clean flask. The resulting solution was re-heated to 60°C. and then cooled slowly, first to room temperature and then to −7° C.The resulting suspension was held at −7° C. and filtered. The filtercake was washed with THF (60 mL) and the solid was dried overnight at50° C. under full vacuum to yield crude mono-succinate salt as a whitesolid.

A suspension of the crude mono-succinate salt (701.3 g, 1.56 mol) inethanol (7.01 L) was heated to 60-65° C. Any insoluble material wasremoved by filtration. The resulting clear solution was cooled slowly to−7° C. The slurry was filtered and washed with ethanol (700 mL). Thefilter cake was dried overnight at 50° C. under full vacuum to yield themono-succinate salt as a white crystalline solid.

M.P.: 154-156° C.

Elemental Analysis For C₁₉H₂₉N₃O₂×C₄H₆O₂:

Calculated: C, 61.45; H, 7.85; N, 9.35; H₂O, <0.1%.

Found: C, 61.42; H, 7.84; N, 9.29; H₂O, <0.1%.

MS: [M+H]⁺=332; [2M+H]⁺=685.

EXAMPLE 7(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanoneMono-fumarate Salt

To a THF solution (40 mL) of(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone(3.0 g, 9.0 mmol) were added THF (40 mL) and fumaric acid (3.3 g, 28.4mmol). The resulting mixture was heated to 60° C. and stirred for 0.5 h.The resulting suspension was cooled to 0° C. and the resultingprecipitate was collected by filtration, washed with THF (20 mL), anddried in a vacuum oven at 65° C. for 20 h to yield crude title compoundas a white solid.

A suspension of crude(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,mono-fumarate (5.7 g, 12.7 mmol) in absolute EtOH (110 mL) was heated to70° C. Any insoluble material was removed by filtration through a Celitepad. The filtrate was reheated to 65° C. and then cooled to 0° C. Theprecipitate was collected by filtration and washed with MTBE (20 mL).The solids were dried in a vacuum oven at 65° C. for 20 h to yield thetitle compound as a white solid.

M.P.: 196-198° C.

Elemental Analysis for C₁₉H₂₉N₃O₂×C₄H₄O₄:

Calculated: C, 61.73; H, 7.43; N, 9.39.

Found: C, 61.44; H, 7.50; N, 9.30.

EXAMPLE 8(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,dihydrochloride monohydrate salt

A solution of (4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone (2.0 g, 6.0 mmol) in absolute EtOH (20 mL) wastreated with HCl_((g)) (0.5 g, 13.7 mmol) at room temperature. Theresulting suspension was stirred for 1 h, and then MTBE (5 mL) wasadded. The suspension was cooled to 0° C. and filtered. The filter cakewas washed with MTBE (20 mL), and the solid was dried in a vacuum ovenat 60° C. for 20 h to yield crude title compound as a white solid.

A suspension of crude(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,dihydrochloride (2.1 g, 5.2 mmol) in absolute EtOH (30 mL) was heated to78° C. and H₂O (2.2 mL) was added. The resulting solution was cooled toroom temperature and MTBE (5 mL) was added. The resulting suspension wascooled to 0° C. and filtered. The filter cake was washed with MeOH (15mL). The solids were dried in a vacuum oven at 105° C. for 20 h to yieldthe title compound as a white solid.

M.P.: decomp >220° C.

Elemental Analysis for C₁₉H₂₉N₃O₂×2HCl×H₂O:

Calculated: C, 53.97; H, 7.81; N, 9.94; Cl, 16.81.

Found: C, 54.13; H, 7.50; N, 9.90; Cl, 16.68; KF: 4.02%.

EXAMPLE 9(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,dihydrobromide semi-hydrate salt

To a THF solution (40 mL) of(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone(3.0 g, 9.0 mmol) were added THF (40 mL) and 30% hydrogen bromidesolution in acetic acid (3.7 mL, 18.6 mmol) while maintaining thetemperature between 15° C. and 20° C. The resulting suspension wasstirred for 1 h, and then cooled to 0° C. The precipitate was collectedby filtration, washed with THF (20 mL), and dried in a vacuum oven at65° C. for 20 h to yield crude title compound as a white solid.

A suspension of crude(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,dihydrobromide (4.9 g, 9.9 mmol) in MeOH (50 mL) was heated to 65° C.The resulting solution was cooled to 0° C. and the precipitate wascollected by filtration and washed with MeOH (15 mL). The solids weredried in a vacuum oven at 65° C. for 20 h to yield the title compound asa white solid.

M.P.: >290° C. decomp

Elemental Analysis for C₁₉H₂₉N₃O₂×2 HBr×0.5H₂O:

Calculated: C, 45.39; H, 6.37; N, 8.36; Br, 31.85.

Found: C, 45.60; H, 6.32; N, 8.36; Br, 33.41.

KF: 2.02%

EXAMPLE 10(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanoneBis-maleate Salt

To a solution of (4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone (3.0 g, 9.05 mmol) in absolute EtOH (20 mL) wasadded, via an addition funnel, a solution of maleic acid (3.3 g, 19.8mmol) in absolute EtOH (20 mL) over 10 min. The resulting suspension wasstirred at room temperature for 15 min, at 75° C. for 30 min, and wasthen allowed to cool to room temperature for 15 h. The reaction mixturewas cooled further to 0° C. and was then stirred for 2 h. The resultingprecipitate was collected by suction filtration and washed with coldEtOH (20 mL). The wet solid was dried in a vacuum oven at 40° C. for 6 hto yield the title compound as crude material, as a white solid.

A suspension of the crude(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,bis-maleate salt (3.0 g) in absolute EtOH (30 mL) was heated at 75° C.for 1 h, and the resulting solution was filtered through a fine porosityglass frit. The filtrate was heated at 75° C. and then cooled to roomtemperature over 2 h, with stirring, and Et₂O (10 mL) was added. Theresulting suspension was cooled to 0° C. for 2 h, the precipitate wascollected by suction filtration and washed with Et₂O (20 mL) undernitrogen protection. The solids were dried in a vacuum oven at 45° C.for 20 h to yield the title compound as a white crystalline solid.

MP: 154.1° C.

Elemental Analysis for C₂₇H₃₇N₃O₁₀:

Calculated: C, 57.54; H, 6.62; N, 7.46.

Found: C, 57.44; H, 6.66; N, 7.33.

EXAMPLE 11 Analysis Protocol for Compounds Prepared as in Examples 12-29

Hewlett Packard HPLC, Zorbax Eclipse XDB-C8, 5 uM, 4.6×150 mm column;Solvents used were H₂O/CH₃CN/0.05% Trifluoroacetic Acid; Gradientconditions were 1% -99% CH₃CN gradient over 8 min, 99% CH₃CN for 2 min.

All reactions were carried out under a nitrogen atmosphere.

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

EXAMPLE 12 1-Isopropyl piperazine dihydrochloride

To a solution of tert-butyl piperazine-1-carboxylate (100 g) and acetone(48 mL) in CH₂Cl₂ (1 L) was added acetic acid (31 mL) and NaBH(OAc)₃(170 g). The reaction mixture was stirred for 18 h, then was dilutedwith 1 N NaOH (500 mL), and extracted with CH₂Cl₂ (500 mL×2). Thecombined organic layers were dried (Na₂SO₄) and concentrated to aresidue. The residue was dissolved in MeOH (200 mL) and 4 M HCl in1,4-dioxane (700 mL) was added to the reaction mixture over a period ofseveral hours. After 18 h, the reaction mixture was concentrated toyield a solid, which was washed with Et₂O (500 mL×2) and dried overnightto yield the title compound as a white solid.

¹H NMR (CD₃OD): 3.76-3.51 (m, 9H), 1.44 (d, J=6.7 Hz, 6H).

EXAMPLE 13 4-Formyl-benzoyl chloride

A suspension of (chloromethylene)dimethylammonium chloride (VilsmeierReagent; 37.7 g, 0.280 mol) in CH₂Cl₂ (300 mL) at 0° C. was treated with4-carboxybenzaldehyde (40.0 g, 267 mmol) in one portion. The reactionmixture was stirred at 0° C. for 30 min, then at room temperature for 2h. HPLC analysis of an aliquot of the reaction mixture quenched intoMeOH indicated consumption of 4-carboxybenzaldehyde. The reactionmixture was filtered through a medium porosity glass frit. The filtrate,containing the title compound, was stored at 0° C., and used in the nextstep without further manipulation.

EXAMPLE 14 4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde

To a suspension of isopropyl piperazine dihydrochloride salt (52.5 g,262 mmol) (prepared as in Example 12 above) in CH₂Cl₂ was added Et₃N(83.5 g, 827 mmol) and the resulting slurry was stirred at roomtemperature for 1 h, then at 0° C. for 30 min. The reaction mixture wasfiltered through a medium porosity glass frit and the filtrate wascooled to 0° C. A solution of 4-formyl benzoyl chloride in CH₂Cl₂ wasadded via an addition funnel in a slow stream over 30 min. The resultingmixture was stirred at 0° C. for 30 min, then at room temperature for 2h. The reaction mixture was cooled to 0° C. and filtered through amedium porosity glass frit. The filtrate was washed with H₂0, 0.5 NNaOH, and brine (1×400 mL each). The organic layer was dried (Na₂SO₄)and concentrated to yield an oil (59.8 g). Trituration of the oil withanhydrous Et₂O (275 mL), followed by removal of the solvent on a rotaryevaporator yielded the title compound as a pale yellow-brown oil.

HPLC: R_(T)=5.43 min.

EXAMPLE 15Hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonicacid sodium salt

A solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (20.0g, 76.9 mmol) in EtOH (200 mL) was stirred at room temperature for 15min. To the resulting solution was added a solution of NaHSO₃ (9.6 g) inH₂O (25 mL), dropwise over 30 min. The resulting suspension was stirredat room temperature for 2 h, then cooled to 0° C. and stirred for 3 h,adding EtOH periodically (total 200 mL) to aid stirring. A precipitateformed and was collected by suction filtration through a glass fritlined with filter paper. The filter cake was washed with hexane (1×50mL), and dried under vacuum for 16 h to yield the title compound as awhite solid.

MP: 275° C. (dec.)

The purity of the compound was determined by dissolution of thebisulfite adduct in 1:1 1 N NaOH/MeOH and analysis by HPLC. In addition,the liberated product was extracted into EtOAc and the organic layeranalyzed by TLC (MeOH/CH₂Cl₂, 1:9). Prolonged exposure in an iodinechamber indicated a single spot (R_(f)=0.71).

EXAMPLE 16 4-(4-Isopropyl-piperazine-1-carbonyl)-benzaldehyde

To a suspension of hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonic acid sodium salt (49.0 g, 135 mmol) inde-ionized H₂O (490 mL) at 0° C. was added 1 N NaOH (100 mL) in 10 mLportions with vigorous stirring. A clear solution resulted (pH 12),which was stirred at 0° C. for 1 h, then at room temperature for 30 min.The aqueous solution was extracted with EtOAc (3×200 mL), followed byCH₂Cl₂ (3×200 mL). The organic layers were combined, washed with brine(1×300 mL), dried (Na₂SO₄) and concentrated to yield the title compoundas a pale yellow oil.

HPLC: R_(T)=5.43 min

MS (ESI): calcd. for C₁₅H₂₀N₂O₂, 260.33; m/z found, 261.1 (M+1)

¹H NMR (CDCl₃): 10.1 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.3 Hz,2H), 3.83 (br s, 2H), 3.41 (br s, 2H), 2.78 (m, 1H), 2.64 (br s, 2H),2.48 (br s, 2H), 1.08 (d, J=6.5 Hz, 6H).

EXAMPLE 17(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

To a solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde(32.0 g, 123 mmol) in THF (650 mL) was added morpholine (21.4 g, 246mmol), in a slow stream via an addition funnel over 15 min, and theresulting mixture was stirred at room temperature for 40 min. Thereaction mixture was treated with NaBH(OAc)₃ (38.4 g, 172 mmol) inportions over 40 min, was stirred at room temperature for 16 h, and thenconcentrated to a residue. The residue was diluted with EtOAc (400 mL),cooled to 0° C., and treated with 1 N NaOH (250 mL). The biphasicsolution stirred at 0° C. for 30 min. The phases were separated and theaqueous layer was extracted with EtOAc (2×200 mL) and CH₂Cl₂ (2×100 mL).The organic layers were combined, washed with brine (1×300 mL), dried(Na₂SO₄), and concentrated to yield the title compound as a pale yellowoil.

HPLC: R_(T)=4.69 min

MS (ESI): calcd. for C₁₉H₂₉N₃O₂, 331.23; m/z found, 332.2 (M+1)

¹H NMR (CDCl₃): 7.36 (s, 4H), 3.79 (br s, 2H), 3.71 (t, J=4.7 Hz, 4H),3.51 (s, 2H), 3.44 (br s, 2H), 2.76-2.69 (m, 1H), 2.59 (br s, 2H), 2.44(t, J=4.4 Hz, 6H), 1.05 (d, J=6.5 Hz, 6H).

EXAMPLE 18(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,bis-maleate salt

To a solution of (4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone (34.0 g, 102.7 mmol) in absolute EtOH (200 mL) wasadded, via an addition funnel, a solution of maleic acid (23.9 g, 206mmol) in absolute EtOH (200 mL) over 15 min. The resulting suspensionwas stirred at room temperature for 30 min, at 75° C. for 1 h, and wasthen allowed to cool to room temperature over 16 h. The reaction mixturewas cooled further to 0° C. and was stirred for 2 h. The reactionmixture was diluted with Et₂O (50 mL) and stirred for 30 min. Theresulting precipitate was collected by suction filtration, washed withcold EtOH/Et₂O (4:1,100 mL×2), and dried in a vacuum oven at 40° C. for20 h to yield the title compound as crude material, as a white solid.

A suspension of the crude(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,bis-maleate salt (90.5 g) in absolute EtOH (905 mL) was heated at 75° C.for 1 h, and the resulting solution was filtered through a fine porosityglass frit. The filtrate was cooled to room temperature over 20 h, withstirring. The resulting suspension was cooled to 0° C. for 2 h, and theprecipitate was collected by suction filtration and washed with Et₂O(2×200 mL). The solids were dried in a vacuum oven at 40° C. for 20 h toyield the title compound as a white crystalline solid.

MP: 148-150° C.

MS (ESI): calcd. for C₁₉H₂₉N₃O₂, 331.23; m/z found, 332.2 (M+1)

¹H NMR (CD₃OD): 7.54-7.48 (m, 4H), 6.26 (s, 4H), 4.23 (s, 2H), 3.85 (brm, 8H), 3.56 (br s, 1H), 3.42-3.32 (br s, 4H), 3.13 (br s, 4H), 1.38 (d,J=6.6 Hz, 6H). Anal. calcd. for C₂₇H₃₇N₃O₁₀: C, 57.54; H, 6.62; N, 7.46.Found: C, 57.52; H, 6.73; N, 7.54.

EXAMPLE 19 4-Formyl-benzoyl chloride

A solution of 4-carboxybenzaldehyde (30.0 g, 0.200 mol) in toluene (300mL) was treated with thionyl chloride (28.6 g, 0.240 mol) and DMF (1.0mL). The reaction mixture was heated at 100° C. for 2 h, during whichtime the solids dissolved to yield a pale yellow colored solution. Thereaction mixture was cooled to 0° C. to yield a solution of the titlecompound in toluene, which was used without further manipulation.

EXAMPLE 20Hydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonicacid sodium salt

A solution of NaOH (24.0 g, 0.600 mol) in de-ionized H₂O (240 mL) andtoluene (60 mL) at 0° C. was treated with isopropyl piperazinedihydrochloride salt (39.0 g, 194 mmol). The resulting biphasic solutionwas stirred at 0° C. for 30 min. A solution of 4-formyl-benzoyl chloridein toluene was added in a slow stream via an addition funnel over 1 h,with vigorous mechanical agitation. The mixture was allowed to warm toroom temperature over 16 h, then cooled to 0° C., and the pH adjusted to10 with 1 N NaOH. The phases were separated and the aqueous layer wasextracted with toluene (2×200 mL). The organic layers were combined,washed with brine (200 mL), and concentrated to yield4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (52.5 g, mass balance101%) as a pale, yellow-brown oil. The oil was dissolved in EtOH (600mL) and, with vigorous mechanical agitation, was treated with a solutionof NaHSO₃ (23.1 g, 222 mmol) in de-ionized H₂O (50 mL) which was addedvia an addition funnel over 30 min. The resulting mixture was stirred atroom tempertaure for 48 h, and then cooled to 0° C. Methyl-tert-butylether (500 mL) was added and the resulting the slurry was stirred for 30min. The precipitate was collected by suction filtration through amedium porosity glass frit, washed with cold EtOH/EtOAc (5:1, 3×60 mL).The solids were dried under vacuum for 2 h, then at 40° C. in a vacuumoven for 16 h to yield the title compound as a white solid.

HPLC: RT=5.43 min

MP: 275° C. (dec.)

EXAMPLE 21(4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone

A mixture ofhydroxy-[4-(4-isopropyl-piperazine-1-carbonyl)-phenyl]-methanesulfonicacid sodium salt (54.6 g, 0.150 mol), piperidine (28.0 g, 0.330 mol),and Montmorillonite-K10 (10.9 g, 20% by wt. relative to startingmaterial) in dichloroethane (820 mL) was stirred at room temperature for16 h. NaBH(OAc)₃ (44.5 g, 210.0 mmol) was added in portions over 1 h,and the resulting suspension was stirred at room temperature for 5 h.Diatomaceous earth (5.4 g) was added and the suspension was stirred foran additional 30 min. The reaction mixture was filtered through a pad ofdiatomaceous earth, rinsing with dichloroethane (2×100 mL). The filtratewas washed with 1 N NaOH (2×200 mL). The aqueous layers were combinedand back-extracted with dichloroethane (2×100 mL). The organic layerswere combined, dried (Na₂SO₄), and concentrated to yield the titlecompound as its corresponding free base, as a pale yellow oil.

HPLC: R_(T)=4.76 min

MS (ESI): calcd. for C₂₀H₃₁N₃O, 329.25; m/z found, 330.2 (M+1)

¹H NMR (CDCl₃): 7.35 (s, 4H), 3.79 (br s, 2H), 3.48 (br s, 2H), 3.45 (brs, 2H), 2.72 (m, 1H), 2.59 (br s, 2H), 2.45 (br s, 2H), 2.38 (br s, 4H),1.60-1.55 (m, 4H), 1.48-1.40 (m, 2H), 1.06 (d, J=6.3 Hz, 6H).

EXAMPLE 22(4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone,bis-maleate salt

To a mechanically agitated solution of(4-isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone(40.0 g, 122 mmol) in absolute EtOH (800 mL) was added, via an additionfunnel, a solution of maleic acid (28.2 g, 243 mmol) in absolute EtOH(200 mL) over 30 min. The resulting suspension was stirred at roomtemperature for 16 h, then diluted with Et₂O (200 mL), cooled to 0° C.,and stirred for 2 h. The precipitate was collected by suctionfiltration, washed with cold EtOH/Et₂O (4:1, 3×100 mL). The solids weredried under vacuum to yield crude title compound as a white solid.

A mechanically agitated suspension of the crude material(4-isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone,bis-maleate salt) (89.0 g) in absolute EtOH (1780 mL) was heated at 75°C. for 1 h. The resulting pale yellow solution was allowed to cool toroom temperature with stirring over 36 h, then diluted with Et₂O (220mL), cooled to 0° C., and stirred for 3 h. The precipitate was collectedby suction filtration, washed with Et₂O (2×100 mL). The solids weredried under vacuum for 16 h to yield the title compound as a whitecrystalline solid.

MP: 165-167° C.

MS (ESI): calcd. for C₂₀H₃₁N₃O, 329.25; m/z found, 330.2 (M+1)

Anal. calcd. for C₂₈H₃₉N₃O₉: C, 59.88; H, 7.00; N, 7.48. Found: C,59.56; H, 7.29; N, 7.40.

EXAMPLE 23 Representative Examples of Reductive Amination of BisulfiteAdducts

Method A

A suspension of benzadehyde bisulfite adduct as listed in Table 3 below(5.0 mmol), Montmorillonite-K10 (0.21 g), and morpholine (10.0 mmol) indichloroethane (20 mL) was stirred at room temperature for 45 min.NaBH(OAc)₃ (7.0 mmol) was added portion-wise over approximately 30 min.After 4 h, the reaction mixture was diluted with EtOAc (80 mL),filtered, and washed with 1N NaOH (25 mL) followed by brine (25 mL). Theorganic layer was dried (MgSO₄) and concentrated to yield4-benzyl-morpholine as an oil. In cases where Montmorillonite K-10 wasnot used, the filtration step after completion of reaction was notnecessary.

General Purification Method

The crude product from Method A was dissolved in EtOAc (50 mL) and theorganic layer was extracted with 1.5 N HCl (25 mL). The aqueous layerwas basified to ca. pH 12 with 1 N NaOH, and extracted with EtOAc (3×50mL). The combined organic layers were dried (MgSO₄) and concentrated toyield the desired product (HPLC Purity >97%).

Method B

A suspension of cyclohexanecarboxaldehyde bisulfite adduct (5.0 mmol)and Et₃ N (5.5 mmol) in dichloroethane (20 mL) was stirred at roomtemperature for 15 min. The suspension was treated withN-methylbenzylamine (5.5 mmol) and was stirred for 45 min. NaBH(OAc)₃(7.0 mmol) was added portion-wise over approximately 30 min. After 16 h,the reaction mixture was diluted with EtOAc (80 mL), and was washed with1 N NaOH (25 mL) followed by brine (25 mL). The organic layer was dried(MgSO₄) and concentrated to yield benzyl-cyclohexylmethyl-methyl-amineas an oil. The crude material was purified by the General PurificationMethod as described above.

Table 9 below lists reductive amination reactions which were completedon representative bisulfite compounds. The column entitled “Reagents”list the reagents or reagent combination used in the reaction to yieldedthe desired product as listed. TABLE 9 Representative Examples ofReductive Amination

Bisulfite Reagent Method Reagents Product

A Morpholine (2.0 equiv.)

A Montmorillonite K-10 +Morpholine (2.0 equiv.)

A Piperidine (2.0 equiv.)

A Montmorillonite K-10 + Piperidine (2.0 equiv.)

B TEA (1.1 equiv.) +Piperidine (1.1 equiv.)

A Pyrrrolidine (2.0 equiv.)

B TEA (1.1 equiv) +Pyrrolidine (1.1 equiv.)

B TEA (1.1 equiv.) +Pyrrolidine (1.1 equiv.)

B TEA (1.1 equiv.) +Diethylamine (1.1 equiv.)

B TEA (1.1 equiv.) +Pyrrolidine (1.1 equiv.)

B TEA (1.1 equiv.) +Morpholine (1.1 Equiv.)

B TEA (1.1 equiv.) +N- Methylbenzyl- amine

B TEA (1.2 equiv.) +3-[4-(1-Acetyl- 2,3-dihydro-1H- indol-6-yl)-3-oxo-4-piperidin-4-yl- butyl]-benzonitrile (0.8 Equiv.)

A Morpholine (2.0 equiv.)

B TEA (1.1 equiv.); Morpholine (1.1 equiv.)

EXAMPLE 24(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

Step A. 4-(4-Formyl-benzoyl)-pirperazine-1-carboxylic acid tert-butylester

A suspension of 4-carboxybenzaldehyde (3.10 g) in CH₂Cl₂ was treatedsequentially with piperazine-1-carboxylic acid tert-butyl ester (3.6 g),EDCl (3.86 g), HOBt (2.68 g), and 4-dimethylaminopyridine (˜0.020 g).After 18 h, the mixture was extracted with 1 N NaOH and then with 1 NHCl. The organic layer was dried (Na₂SO₄) and concentrated to yield thetitle compound.

MS (ESI): mass calcd. for C₁₇H₂₂N₂O₄, 318.16; m/z found, 219.3[(M−100)+H]⁺

¹H NMR (CDCl₃): 10.04 (s, 1H), 7.93 (d, J=8.2, 2H), 7.54 (d, J=8.1, 2H),3.82-3.67 (m, 2H), 3.58-3.30 (m, 6H), 1.46 (s, 9H).

Step B. 4-(4-Morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylic acidtert-butyl ester

A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic acidtert-butyl ester (2.06 g) in methanol (100 mL) was treated withmorpholine (4 mL) and NaBH(OAc)₃ (6.98 g, in portions over 1 h). After 3h, the mixture was diluted with saturated aquoues NaHCO₃ and extractedwith CH₂Cl₂. The organic layer was dried (Na₂SO₄) and concentrated. Theresidue was purified by column chromatography (SiO₂) to yield the titlecompound.

MS (ESI): mass calcd. for C₂₁H₃₁N₃O₄, 389.23; m/z found, 390.4 [M+H]⁺.

¹H NMR (CDCl₃): 7.39-7.33 (m, 4H), 3.75-3.66 (m, 6H), 3.50 (s, 2H),3.51-3.33 (m, 6H), 2.45-2.41(m, 4H), 1.46 (s, 9H).

Step C. (4-Morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone

A solution of 4-(4-morpholin-4-ylmethyl-benzoyl)-piperazine-1-carboxylicacid tert-butyl ester (1.163 g) in CH₂Cl₂ (10 mL) was treated withtrifluoroacetic acid (˜4 mL). After 30 min, additional trifluoroaceticacid (5 mL) was added, and the mixture was stirred for a further 2 h.The mixture was diluted with diluted with saturated aquoues NaHCO₃ andextracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) andconcentrated. The residue was purified by column chromatography (SiO₂)to yield the title compound.

MS (ESI): mass calcd. for C₁₆H₂₃N₃O₂, 289.18; m/z found, 290.4 [M+H]⁺

¹H NMR (CDCl₃): 7.41-7.35 (m, 4H), 3.95-3.70 (m, 6H), 3.52 (s, 2H),3.09-2.80 (m, 6H), 2.49-2.42 (m, 4H).

Step D.(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

A solution of (4-morpholin-4-ylmethyl-phenyl)-piperazin-1-yl-methanone(0.128 g) in methanol (7.5 mL) was treated with(1-ethoxy-cyclopropoxy)-trimethyl-silane (1.5 mL), acetic acid (0.2 mL),and NaBH₃CN (˜400 mg). The mixture was heated at 60° C. for 18 h, andthen was cooled to room temperature and concentrated. The residue wasdiluted with 1 N NaOH and extracted with CH₂Cl₂. The organic layer wasdried (Na₂SO₄) and concentrated. The residue was purified by columnchromatography (SiO₂) to yield the title compound.

MS (ESI): mass calcd. for C₁₉H₂₇N₃O₂, 329.21; m/z found, 330.4 [M+H]⁺

¹H NMR (CDCl₃): 7.36 (s, 4H), 3.79-3.68 (m, 6H), 3.50 (s, 2H), 3.44-3.32(m, 2H), 2.74-2.61(m, 2H), 2.60-2.50 (s, 2H), 2.45-2.40 (m, 4H),1.66-1.62 (m, 1H), 0.49-0.44 (m, 2H), 0.44-0.39 (m, 2H).

EXAMPLE 25(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

Step A. tert-Butyl 4-cyclopropylpiperazine-1-carboxylate

A mixture of tert-butyl piperazine-1-carboxylate (75.0 g), THF (500 mL),methanol (500 mL), [(1-ethoxycyclopropyl)oxy]trimethylsilane (161 mL),NaBH₃CN (38.0 g), and acetic acid (37 mL) was heated at 60° C. for 5 h.The mixture was cooled to room temperature, treated with water (30 mL)and stirred for 5 min. The mixture was then treated with 1 N NaOH (130mL) and was further stirred for 15 min. The mixture was concentrated,and the remaining aqueous solution was extracted with CH₂Cl₂ (500 mL).The organic layer was washed with 1 N NaOH (500 mL). The combinedaqueous layers were extracted with CH₂Cl₂ (150 mL). The combined organiclayers were washed with brine (400 mL), dried (Na₂SO₄), and concentratedto yield the title compound as a white solid.

MS (ESI): mass calcd. for C₁₂H₂₂N₂O₂, 226.17; m/z found, 227.2 [M+H⁺]

¹H NMR (400 MHz, CDCl₃): 3.39 (t, J=5.0 Hz, 4H), 2.55 (t, J=4.9 Hz, 4H),1.60 (ddd, J=10.3, 6.5, 3.8 Hz, 1H), 1.46 (s, 9H), 0.49-0.38 (m, 4H).

Step B. 1-Cyclopropylpiperazine dihydrochloride

A solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (92 g) in1,4-dioxane (200 mL) was treated with HCl (4 M in 1,4-dioxane, 500 mL)over 10 min while maintaining the temperature below 40° C. After theaddition was complete, the mixture was heated at 45° C. for 9 h and thenwas cooled to room temperature. The thick suspension was diluted withhexanes (400 mL) and was cooled to 10° C. The resulting solid wascollected by filtration, washed with hexanes, and dried to yield thetitle compound as a white solid.

MS (ESI): mass calcd. for C₇H₁₄N₂, 126.12; m/z found, 127.0 [M+H⁺]

¹H NMR (400 MHz, D₂O): 3.65 (br t, J=4.7 Hz, 4H), 3.47 (br t, J=5.5 Hz,4H), 2.85 (br quintet, J=5.8 Hz, 1H), 0.94 (br s, 2H), 0.92 (br s, 2H).

Step C. 4-(4-Cyclopropyl-piperazine-1-carbonyl)-benzaldehyde

A mixture of 4-formyl-benzoic acid (54.4 g), toluene (500 mL), DMF (3.6mL), and thionyl chloride (30.4 mL) was heated at 60° C. for 2 h andthen was cooled to 5° C. In a separate flask, a 5° C. mixture of NaOH(50.7 g), water (550 mL), and toluene (150 mL) was treated with1-cyclopropyl-piperazine dihydrochloride (70.0 g) in portions while thetemperature was maintained below 10° C. After the addition was complete,the mixture was cooled to 5° C. and treated with the crude acyl chloridesolution prepared as above at a rate such that the temperature did notexceed 10° C. After the addition was complete, the mixture was allowedto warm to room temperature and was stirred overnight. The biphasicmixture was basified to pH˜10 with 1 N NaOH (300 mL). The layers wereseparated and the aqueous layer was extracted with toluene (100 mL×2).The combined organic layers were washed with brine (200 mL), dried(Na₂SO₄), and concentrated to yield the title compound as pale yellowviscous oil.

HPLC: R_(T)=5.19 min

MS (ESI): mass calcd. for C₁₅H₁₈N₂O₂, 258.14; m/z found, 258.9 [M+H⁺]

¹H NMR (400 MHz, CDCl₃): 10.1(s, 1H), 7.94 (pseudo d, J=8.2 Hz, 2H),7.56 (pseudo d, J=8.1 Hz, 2H), 3.77 (br s, 2H), 3.33 (br s, 2H), 2.71(brs, 2H), 2.55 (br s, 2H), 1.66 (ddd, J=10.2, 6.6, 3.7 Hz, 1H), 0.52-0.46(m, 2H), 0.45-0.40 (br s, 2H).

Step D.(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

To a solution of 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde(56.0 g) in 1,2-dichloroethane (550 mL) was added morpholine (37.8 mL)dropwise over 5 min. The mixture was cooled to 10° C. and was treatedwith NaBH(OAc)₃ (64.3 g) in portions over 1 h. After a further 2 h, themixture was warmed to room temperature, and a water bath was used tokeep the temperature below 20° C. After 18 h, water (60 mL) was addedwhile the temperature was kept under 20° C. by the addition of smallamounts of ice. After 20 min, the mixture was basified to pH˜10 with 1 NNaOH (450 mL) and the mixture was stirred for 10 min. The layers wereseparated, and the organic layer was washed with 1 N NaOH (150 mL). Thecombined aqueous layers were extracted with CH₂Cl₂ (200 mL). Thecombined organic layers were washed with brine (200 mL), dried (Na₂SO₄),and concentrated to yield the title compound as pale yellow viscous oil.

HPLC: R_(T)=4.39 min

MS (ESI): mass calcd. for C₁₉H₂₇N₃O₂, 329.21; m/z found, 330.2 [M+H⁺]

¹H NMR (400 MHz, CDCl₃): 7.35 (br s, 4H), 3.73 (br s, 2H), 3.69 (t,J=4.6 Hz, 4H), 3.50 (s, 2H), 3.37 (br s, 2H), 2.67 (br s, 2H), 2.53 (brs, 2H), 2.43 (t, J=4.2 Hz, 4H), 1.63 (ddd, J=10.3, 6.7, 3.7 Hz, 1H),0.49-0.43 (m, 2H), 0.42-0.39 (br s, 2H).

¹³C NMR (101 MHz, CDCl₃): 170.6, 140.0, 135.1, 129.5, 127.5, 67.4, 63.4,54.0, 38.7, 6.3.

EXAMPLE 26(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanonedihydrochloride salt

A solution of(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone(68.0 g) in ethanol (400 mL) was heated to 60° C. and treated withconcentrated HCl (37.8 mL) dropwise over 40 min. A precipitate startedto form after ˜20 mL of HCl had been added. After the addition wascomplete, the thick suspension was slowly cooled to 20° C. over 3 h. Thesolid was collected by filtration, washed with ethanol, and dried at 50°C. overnight in a vacuum oven to provide the title compound as a whitesolid.

HPLC: R_(T)=4.30 min

MS (ESI): mass calcd. for C₁₉H₂₇N₃O₂, 329.21; m/z found, 330.0 [M+H⁺]

¹H NMR (400 MHz, D₂O): 7.64 (pseudo d, J=8.3 Hz, 2H), 7.58 (pseudo d,J=8.3 Hz, 2H), 4.44 (br s, 2H), 4.20-3.10 (m, 16H), 2.88 (ddd, J=11.2,6.6, 4.8 Hz, 1H), 1.03-0.98 (m, 4H)

¹³C NMR (101 MHz, D₂O): 172.1, 135.3, 132.2, 130.9, 128.0, 64.0, 60.5,52.6, 52.4, 51.7, 44.8, 39.7, 39.5, 3.9.

EXAMPLE 27(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

Preparation and analytical data for the title compound was presented inU.S. Patent Application Publication 2004-0110746 A1, published Apr. 21,2005.

EXAMPLE 28(4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

The title compound was prepared according to the methods described inExample 23 above.

EXAMPLE 29 Sodium[4-(4-Cyclopropyl-piperazine-1-carbonyl)-phenyl]-hydroxy-methanesulfonate

A 100 mL flask was charged with4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (2.58 g, 10.0 mmol,1.0 eq), acetonitrile (30 mL), and water (1.0 mL) under nitrogenatmosphere. The reaction mixture was heated to 50° C. A solution ofNaHSO₃ (1.14 g, 11.0 mol, 1.1 eq) in water (2.0 mL) was added dropwiseover 5 min. The reaction mixture was then cooled to 17° C. The productwas collected by filtration as a white solid.

¹H-NMR (400 MHz, D₂O): δ 7.66 (pseudo d, 2H, J=8.1 Hz), 7.47 (pseudo d,2H, J=8.2 Hz), 5.58 (s, 1H), 3.74 (br s, 2H), 3.47 (br s, 2H), 2.84 (brs, 2H), 2.69 (br s, 2H), 1.85 (tt, 1H, J=7.0, 3.8 Hz), 0.60-0.54 (m,2H), 0.49-0.44 (m, 2H)

MS (ESI-): mass calculated for C₁₅H₁₉N₂O₅S, 339.1; m/z found, 339.0[M−Na]⁻.

EXAMPLE 30

As a specific embodiment of an oral composition, 100 mg of the compoundprepared as in Example 6 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size O hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A process for the preparation of a compound of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof; wherein R¹ is selected from the group consisting ofC₁₋₁₀alkyl, C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl,(C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈alkylcarbonyl)C₁₋₈alkyl; n is aninteger from 1to 2; R² and R³ are each independently selected fromhydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, orC₁₋₃alkoxy; m is an integer from 1to 7; Q is NR⁸R⁹; wherein R⁸ isselected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,3-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,(6-9-membered heterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene; and R⁹is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl, 6-9membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene; alternatively, Qis a saturated 3-12 membered N-linked heterocyclyl, wherein, in additionto the N-linking nitrogen, the 3-12 membered heterocyclyl may optionallycontain between 1 and 3 additional heteroatoms independently selectedfrom O, S, and NH; wherein Q (when Q is a saturated 3-12 memberedN-linked heterocyclyl) is optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydroxy, halo,carboxamide, C₁₋₆alkyl, 5-9 membered or 6-9 membered heterocyclyl,—N(C₁₋₆ alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 memberedheterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C₁₋₃alkylene,C₁₋₆alkoxy, (C₃₋₆cycloalkyl)—O—, phenyl, (phenyl)C₁₋₃ alkylene, and(phenyl)C₁₋₃alkylene-O—; where each of the above heterocyclyl, phenyl,and alkyl groups may be further optionally substituted with from 1 to 3substituents independently selected from the group consisting oftrifluoromethyl, methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;provided that the 5- and 6- positions on the phenyl ring areunsubstituted; provided further that when R¹ is methyl, then —(CH₂)m-Qis not piperidin-1-ylmethyl; and wherein each of the above alkyl,alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and arylgroups may each be independently and optionally substituted with between1 and 3 substituents independently selected from the group consisting oftrifluoromethyl, methoxy, halo, amino, nitro, hydroxy and C₁₋₃ alkyl;comprising

reacting a compound of formula (X); in a first organic solvent; to yieldthe corresponding compound of formula (XI), wherein L is a leavinggroup; and wherein the compound of formula (XI) is not isolated;

reacting the compound of formula (XI) with a compound of formula (XII);in the presence of an organic or inorganic base; in a second organicsolvent; to yield the corresponding compound of formula (XIII); whereinthe compound of formula (XIII) is not isolated;

and reacting the compound of formula (XIII) with a compound of formula(XIV); in the presence of a reducing agent; in a third organic solvent;to yield the corresponding compound of formula (I).
 2. A process as inclaim 1, wherein the first organic solvent, the second organic solventand the third organic solvent are the same.
 3. A process as in claim 1,wherein L is chloro.
 4. A process as in claim 1, further comprisingreacting the compound of formula (I) to yield the correspondingpharmaceutically acceptable salt of the compound of formula (I).
 5. Aprocess as in claim 4, wherein the pharmaceutically acceptable salt isselected from the group consisting of succinate, fumarate, maleate,hydrochlororide or hydrobromide salt.
 6. A process as in claim 1,wherein the compound of formula (I) is a compound of formula (Ia)

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt, ester or amide thereof.
 7. A process as in claim 1wherein R¹ is isopropyl; n is 1; R² is hydrogen; R³ is hydrogen and R⁴is 4-morpholinyl-methyl-.
 8. A process for the preparation of a compoundof formula (Is)

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt, ester or amide thereof; comprising

reacting a compound of formula (Xs); in a first organic solvent; toyield the corresponding compound of formula (XIs), wherein L is aleaving group; and wherein the compound of formula (XIs) is notisolated;

reacting the compound of formula (XIs) with a compound of formula(XIIs); in the presence of an organic or inorganic base; in a secondorganic solvent; to yield the corresponding compound of formula (XIIIs);wherein the compound of formula (XIIIs) is not isolated;

and reacting the compound of formula (XIIIs) with a compound of formula(XIVs); in the presence of a reducing agent; in a third organic solvent;to yield the corresponding compound of formula (Is).
 9. A process as inclaim 8, wherein the first organic solvent, the second organic solventand the third organic solvent are the same.
 10. A process as in claim 8,wherein L is chloro.
 11. A process as in claim 8, wherein the compoundof formula (XIIs) is present in an amount equal to about one equivalent.12. A process as in claim 8, wherein the compound of formula (XIVs) ispresent in an amount greater than about one equivalent; and wherein thereducing agent is present in an amount in the range of from about 1 toabout 2 equivalents.
 13. A process as in claim 8, further comprisingreacting the compound of formula (Is) to yield the correspondingpharmaceutically acceptable salt of the compound of formula (Is).
 14. Aprocess as in claim 13, wherein the pharmaceutically acceptable salt isselected from the group consisting of succinate, fumarate, maleate,hydrochlororide or hydrobromide salt.
 15. A process as in claim 13,wherein the pharmaceutically acceptable salt is a mono-succinate salt.16. A process for the preparation of a compound of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof; wherein R¹ is selected from the group consisting ofC₁₋₁₀alkyl, C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl,(C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈ alkylcarbonyl)C₁₋₈alkyl; n is aninteger from 1 to 2; R² and R³ are each independently selected fromhydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, orC₁₋₃alkoxy; m is an integer from 1 to 7; Q is NR⁸R⁹; wherein R⁸ isselected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,3-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,(6-9-membered heterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene; and R⁹is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl, 6-9membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene; alternatively, Qis a saturated 3-12 membered N-linked heterocyclyl, wherein, in additionto the N-linking nitrogen, the 3-12 membered heterocyclyl may optionallycontain between 1 and 3 additional heteroatoms independently selectedfrom O, S, and NH; wherein Q (when Q is a saturated 3-12 memberedN-linked heterocyclyl) is optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydroxy, halo,carboxamide, C₁₋₆alkyl, 5-9 membered or 6-9 membered heterocyclyl,—N(C₁₋₆ alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 memberedheterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C₁₋₃alkylene,C₁₋₆alkoxy, (C₃₋₆cycloalkyl)—O—, phenyl, (phenyl)C₁₋₃ alkylene, and(phenyl)C₁₋₃alkylene-O—; where each of the above heterocyclyl, phenyl,and alkyl groups may be further optionally substituted with from 1 to 3substituents independently selected from the group consisting oftrifluoromethyl, methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;provided that the 5- and 6-positions on the phenyl ring areunsubstituted; provided further that when R¹ is methyl, then—(CH₂)_(m)-Q is not piperidin-1-ylmethyl; and wherein each of the abovealkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, andaryl groups may each be independently and optionally substituted withbetween 1 and 3 substituents independently selected from the groupconsisting of trifluoromethyl, methoxy, halo, amino, nitro, hydroxy andC₁₋₃ alkyl; comprising

reacting a compound of formula (XIII) with a source of bisulfite; in apolar organic solvent; to yield the corresponding compound of formula(XVII);

and reacting the compound of formula (XVII) with a compound of formula(XIV); in the presence of a reducing agent; in the presence of anorganic or inorganic base; in an organic solvent; to yield thecorresponding compound of formula (I).
 17. A process as in claim 16,wherein the source of bisulfite is present in an amount greater than orequal to about one equivalent.
 18. A process as in claim 16, where thecompound of formula (XIV) is present in an amount greater than about oneequivalents.
 19. A process as in claim 16, wherein the compound offormula (XIV) is present in an amount equal to or greater than about 2equivalents and wherein about one equivalent of the compound (XIV) actsas the organic or inorganic base.
 20. A process as in claim 16, whereinthe compound of formula (XVII) is isolated by filtration.
 21. A processas in claim 16, further comprising reacting the compound of formula (I)to yield the corresponding pharmaceutically acceptable salt of thecompound of formula (I).
 22. A process as in claim 21, wherein thepharmaceutically acceptable salt is selected from the group consistingof succinate, fumarate, maleate, hydrochlororide or hydrobromide salt.23. A process as in claim 16, wherein the compound of formula (I) is acompound of formula (Ia)

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt, ester or amide thereof.
 24. A process as in claim 16,wherein R¹ is isopropyl; n is 1; R² is hydrogen; R³ is hydrogen and R⁴is 4-morpholinyl-methyl-.
 25. A process for the preparation of acompound of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof; wherein R¹ is selected from the group consisting ofC₁₋₁₀alkyl, C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl,(C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈ alkylcarbonyl)C₁₋₈alkyl; n is aninteger from 1 to 2; R² and R³ are each independently selected fromhydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, orC₁₋₃alkoxy; m is an integer from 1 to 7; Q is NR⁸R⁹; wherein R⁸ isselected from the group consisting of hydrogen, C₁₋₆alkyl, C₃₋₆alkenyl,3-9 membered carbocyclyl, 3-12 membered heterocyclyl, phenyl,(6-9-membered heterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene; and R⁹is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl, 6-9membered carbocyclyl, 3-12 membered heterocyclyl, phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene; alternatively, Qis a saturated 3-12 membered N-linked heterocyclyl, wherein, in additionto the N-linking nitrogen, the 3-12 membered heterocyclyl may optionallycontain between 1 and 3 additional heteroatoms independently selected O,S, and NH; wherein Q (when Q is a saturated 3-12 membered N-linkedheterocyclyl) is optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydroxy, halo,carboxamide, C₁₋₆alkyl, 5-9 membered or 6-9 membered heterocyclyl,—N(C₁₋₆ alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9membered or 6-9 membered heterocyclyl), —O(5-9 or 6-9 memberedheterocyclyl), (5-9 membered or 6-9 membered heterocyclyl)C₁₋₃alkylene,C₁₋₆alkoxy, (C₃₋₆cycloalkyl)—O—, phenyl, (phenyl)C₁₋₃ alkylene, and(phenyl)C₁₋₃alkylene O—; where each of the above heterocyclyl, phenyl,and alkyl groups may be further optionally substituted with from 1 to 3substituents independently selected from the group consisting oftrifluoromethyl, methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;provided that the 5- and 6-positions on the phenyl ring areunsubstituted; provided further that when R¹ is methyl, then—(CH₂)_(m)-Q is not piperidin-1-ylmethyl; and wherein each of the abovealkyl, alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, andaryl groups may each be independently and optionally substituted withbetween 1 and 3 substituents independently selected from the groupconsisting of trifluoromethyl, methoxy, halo, amino, nitro, hydroxy andC₁₋₃ alkyl; comprising

reacting a compound of formula (XIII) with a source of bisulfite; in apolar organic solvent; to yield the corresponding compound of formula(XVII);

reacting the compound of formula (XVII) with an organic or inorganicbase; in an organic solvent; to yield the corresponding compound offormula (XIII);

and reacting the compound of formula (XIII) with a compound of formula(XIV); in the presence of a reducing agent; in an organic solvent; toyield the corresponding compound of formula (I).
 26. A process as inclaim 25, wherein the organic or inorganic base in present in an amountgreater than or equal to about 1 equivalent.
 27. A process as in claim25, wherein the compound of formula (XIV) is present in an amountgreater than or equal to about one equivalent; and wherein the reducingagent is present in an amount in the range of from about 1 to about 2equivalents.
 28. A process as in claim 25, wherein the compound offormula (XVII) is isolated by filtration.
 29. A process as in claim 25,further comprising reacting the compound of formula (I) to yield thecorresponding pharmaceutically acceptable salt of the compound offormula (I).
 30. A process as in claim 29, wherein the pharmaceuticallyacceptable salt is selected from the group consisting of succinate,fumarate, maleate, hydrochlororide or hydrobromide salt.
 31. A processas in claim 25, wherein the compound of formula (I) is a compound offormula (Ia)

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt, ester or amide thereof.
 32. A process as in claim 25,wherein R¹ is isopropyl; n is 1; R² is hydrogen; R³ is hydrogen and R⁴is 4-morpholinyl-methyl-.
 33. A process for the preparation of acompound of formula (Is)

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt, ester or amide thereof; comprising

reacting a compound of formula (XIIIs) with a source of bisulfite; in apolar organic solvent; to yield the corresponding compound of formula(XVIIs);

and reacting the compound of formula (XVIIs) with a compound of formula(XIVs); in the presence of a reducing agent; in the presence of anorganic or inorganic base; in an organic solvent; to yield thecorresponding compound of formula (Is).
 34. A process as in claim 33,wherein the source of bisulfite is present in an amount greater than orequal to about one equivalent.
 35. A process as in claim 33, where thecompound of formula (XIVs) is present in an amount greater than aboutone equivalents.
 36. A process as in claim 33, wherein the compound offormula (XIVs) is present in an amount equal to or greater than about 2equivalents and wherein about one equivalent of the compound (XIVs) actsas the organic or inorganic base.
 37. A process as in claim 33, whereinthe compound of formula (XVIIs) is isolated by filtration.
 38. A processas in claim 33, further comprising reacting the compound of formula (Is)to yield the corresponding pharmaceutically acceptable salt of thecompound of formula (Is).
 39. A process as in claim 38, wherein thepharmaceutically acceptable salt is selected from the group consistingof succinate, fumarate, maleate, hydrochlororide or hydrobromide salt.40. A process as in claim 38, wherein the pharmaceutically acceptablesalt is a mono-succinate salt.
 41. A process for the preparation of acompound of formula (Is)

or an enantiomer, diastereomer, hydrate, solvate, or pharmaceuticallyacceptable salt, ester or amide thereof; comprising

reacting a compound of formula (XIIIs) with a source of bisulfite; in apolar organic solvent; to yield the corresponding compound of formula(XVIIs);

reacting the compound of formula (XVIIs) with an organic or inorganicbase; in an organic solvent; to yield the corresponding compound offormula (XIIIs);

and reacting the compound of formula (XIIIs) with a compound of formula(XIVs); in the presence of a reducing agent; in an organic solvent; toyield the corresponding compound of formula (Is).
 42. A process as inclaim 41, wherein the organic or inorganic base in present in an amountgreater than or equal to about 1 equivalent.
 43. A process as in claim41, wherein the compound of formula (XIVs) is present in an amountgreater than or equal to about one equivalent; and wherein the reducingagent is present in an amount in the range of from about 1 to about 2equivalents.
 44. A process as in claim 41, wherein the compound offormula (XVIIs) is isolated by filtration.
 45. A process as in claim 41,further comprising reacting the compound of formula (Is) to yield thecorresponding pharmaceutically acceptable salt of the compound offormula (Is).
 46. A process as in claim 45, wherein the pharmaceuticallyacceptable salt is selected from the group consisting of succinate,fumarate, maleate, hydrochlororide or hydrobromide salt.
 47. A processas in claim 45, wherein the pharmaceutically acceptable salt is amono-succinate salt.
 48. A crystalline succinate salt of(4-isopropyl-piperazin-1-yl)—(4-morpholin-4-ylmethyl-phenyl)-methanone.49. The salt of claim 48, wherein the succinate salt is a mono-succinatesalt.
 50. A crystalline mono-succinate salt of(4-isopropyl-piperazin-1-yl)—(⁴-morpholin-4-ylmethyl-phenyl)-methanonecomprising the following X-ray diffraction peaks: Position [°2θ]d-spacing [Å] 8.782 10.0698 13.161 6.7274 14.587 6.0728 15.961 5.552717.308 5.1237 17.555 5.0520 19.767 4.4915 20.210 4.3941 20.415 4.350323.802 3.7383 26.429 3.3728


51. A crystalline mono-succinate salt of(4-isopropyl-piperazin-1-yl)—(4-morpholin-4-ylmethyl-phenyl)-methanonecomprising the following X-ray diffraction peaks: Position [°2θ]d-spacing [Å] 8.782 10.0698 13.161 6.7274 17.555 5.0520 23.802 3.738326.429 3.3728


52. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 49. 53. A pharmaceuticalcomposition made by mixing a compound of claim 49 and a pharmaceuticallyacceptable carrier.
 54. A process for making a pharmaceuticalcomposition comprising mixing a compound of claim 49 and apharmaceutically acceptable carrier.